Selective antagonists of A2A adenosine receptors

ABSTRACT

Selective antagonists of A 2A  adenosine receptors like those of formula I are provided, wherein Y forms a ring. 
                         
The novel A 2A  blockers are useful for the treatment of Parkinsons disease and other diseases.

This application claims the benefit of U.S. Provisional Application No.60/559,159, filed Apr. 2, 2004, entitled “Selective Antagonists of A2AAdenosine Receptors” the disclosure of which is incorporated herein inits entirety.

FIELD OF THE INVENTION

The present invention relates to compounds and pharmaceuticalcompositions that are selective antagonists of the A_(2A) adenosinereceptor (AR). These compounds are useful as pharmaceutical agents.

Selective antagonists of A_(2A) adenosine receptors have proven to beeffective for the treatment of Parkinson's disease (PD) both in animalmodels and in a human trial.¹ However, the initial clinical trial wasstopped in phase 3 due to detection of animal toxicity of theinvestigational drug, KW6002. Other investigational compounds lacksufficient potency, selectivity or bioavaility to be considered clinicalcandidates.

BACKGROUND OF THE INVENTION

Parkinson's disease is the second most common neurodegenerative disorderand affects over 1 million people in North America.² The pathologicalprocess, degeneration of the dopaminergic neurons in the substantialnigra, causes profound depletion of striatal dopamine and motorimpairment. This insight led to the introduction of L-dopa as adopamine-replacement treatment for PD.³ Today, L-dopa continues to bethe “Gold Standard” treatment for the motor symptoms of PD.^(4,5)Despite the considerable symptomatic relief it affords, long-termtreatment with L-dopa has major limitations.⁶ After five to ten years oftreatment with L-dopa, up to 60% of patients experience loss of L-dopaeffectiveness and some debilitating complications,^(7,8) notably, an“on” and “off” motor fluctuation and involuntary choreic or dystonicmovements, dyskinesia. This has become the limiting factor in managementof patients in the later stages of PD.⁹ The development of dyskinesiamight reflect desensitization of dopamine receptors.¹⁰ Most importantly,there is no clear evidence that L-dopa slows or halts the degenerationof dopaminergic neurons. In fact, in vitro cell culture studiessuggested that dopamine and its oxidative metabolites are toxic todopaminergic neurons, and raised the concern that L-dopa may actuallyaccelerate the degeneration of dopaminergic neurons. Because of thisconcern, many clinicians avoid prescribing L-dopa early in the course ofPD.¹¹

These major limitations of L-dopa therapy are linked to the activationof dopamine receptors. This has prompted a search for alternativetreatment for PD not targeting the dopaminergic system.¹² Striatalneuromodulators and transmitters other than dopamine are increasinglyappreciated as critical regulators of motor function and offer newtherapeutic opportunities to complement dopamine-replacement.

Over the last 10 years, the A_(2A) adenosine receptor (A_(2A)AR) hasreceived increasing attention as a treatment for PD.^(13,14) Thiscontention is based on our understanding of the role of the A_(2A)AR inthe basal ganglia and on the recent development of new, more selectiveA_(2A)AR antagonists. Anatomical, neurochemical and behavioral evidenceof adenosine-dopamine interactions underlie this new therapeuticapproach.¹⁵⁻¹⁷ Anatomically, A_(2A)AR density is high in the striatum,where receptor mRNA is co-expressed with D₂ receptor mRNA in thestriatopallidal neurons.¹⁸⁻²⁰ This unique cellular distribution ofA_(2A) receptors suggests that A_(2A) receptor antagonists canselectively modulate the “indirect” striatopallidal pathway to affectmotor activity. At the neurochemical level, activation of the A_(2A)ARreduces the binding affinity of D₂ receptors in the striatum,²¹ andantagonizes many neurochemical and cellular changes brought about by theactivation of striatal D₂ receptors, including release of acetylcholineand GABA and expression of c-Fos. Furthermore, behavioral studies havedemonstrated that the unselective adenosine antagonists caffeine andtheophylline stimulate locomotor activity^(22,23) whereas theunselective agonist NECA²⁴ inhibits spontaneous locomotor activity aswell as motor activity induced by dopamine agonists. Thus, A_(2A)ARagonists and antagonists function as dopamine antagonists and agonists,respectively, in modulating motor activity. The three possiblemechanisms have been proposed to explain for motor enhancement by theA_(2A) antagonists: (1) a direct receptor-receptor (A_(2A)-D₂)antagonistic interaction,^(25,26) (2) an opposing but independent ofA_(2A) and D₂ receptor signaling²⁷⁻²⁹ or (3) A_(2A)AR modulation of GABArelease in the basal ganglia.³⁰⁻³² These receptors also form A_(2A)AR-D2heterodimers,³³ but how dimerization affects receptor function isunclear.

A_(2A) Receptor Antagonists May Offer Multiple Therapeutic Benefits forPD Patients

First, A_(2A) antagonists stimulate motor activity in normal as well asdopamine-depleted animals. In rodent models of PD, unselective adenosineantagonists (caffeine and theophylline)^(22,34) and theA_(2A)AR-selective antagonists SCH58261, KW6002 and CSC can reversemotor deficits induced by MPTP, 6-hydroxydopamine, haloperidol orreserpine³⁵⁻⁴¹ as well as by genetic deletion of D₂ receptors.⁴² Morerecently, the A_(2A) antagonists KW6002 reversed motor deficit inMPTP-treated non-human primates.^(43,44) Furthermore, A_(2A) antagonistscan stimulate motor activity when combined with sub-threshold doses ofdopaminergic agents such as L-dopa or D₁ and D₂ agonists such asaporphormine or quinpirole.⁴⁵ For example, combining KW6002 with L-dopareduces the dose of L-dopa, thereby reducing the complicationsassociated with L-dopa. In contrast to some non-specific adenosineantagonists or some dopamine agonists, motor stimulation was observedafter acute treatment and persisted following treatment continued for 15days.^(44,46,47) Thus, tolerance to the motor stimulant effect of A_(2A)antagonists did not develop.

Second, studies of the MPTP-treated monkey model of PD revealed a novelfeature of A_(2A) antagonists, namely, stimulation of motor activitywithout dyskinesia.^(43,44,48) In contrast to L-dopa, repeated treatmentwith KW6002 reversed the motor deficit but did not induce dyskinesia,even in monkeys primed with L-dopa. Further, our recent findings inA_(2A)AR knockout mice suggest that development of behavioralsensitization by chronic treatment of L-dopa requires activation of theA_(2A)AR. Genetic inactivation of the A_(2A) receptor attenuatedL-dopa-induced rotational behavior.⁴⁹ This is consistent with a recentstudy showing that co-administration of KW6002 with apomorphine toMPTP-treated monkeys completely abolished the development ofapomorphine-induced dyskinesia.⁵⁰ Further studies are warranted toexplore the molecular mechanism underlying this novel aspect of A_(2A)ARfunction.

Third, accumulating evidence suggests that the specific inactivation ofA_(2A)ARs consistently attenuates brain damage induced byischemia^(51,53) and excitoxicity,^(54,55) as well as in animal modelsof Huntington's disease⁵⁶ and Alzheimer's disease.⁵⁷ The neuroprotectionby A_(2A)AR antagonists has been recently extended to a rodent model ofPD. Co-administration of A_(2A)AR antagonists, such as CSC, DMPX,SCH58261 and KW6002 (but not the A₁AR antagonist DPCPX) attenuateddopaminergic neurotoxicity in several neurotoxin models of PD.⁵⁸A_(2A)AR antagonists provided not only functional protection (such asreduced dopamine content and expression of molecular markers for thedopaminergic terminals), but also reduced the loss of dopaminergicneurons in substantia nigra in both MPTP- and 6-OHDA models ofPD.^(59,60) Likewise, knockout of A_(2A)ARs attenuated MPTP-induceddopaminergic neurotoxicity in mice.⁵⁹ Together with the demonstration ofneuroprotection by A_(2A)AR antagonists against a wide range of neuronalinjury models. These results raise the possibility that A_(2A)antagonists may offer a neuroprotection, slowing or even haltingdegeneration of dopaminergic neurons.

Finally, in contrast to the widespread distribution of otherneurotransmitter receptors, for example, glutamate receptors, theexpression of the A_(2A)AR is almost exclusively in striatum, whichmight allow selective modulation of dopamine-mediated motor pathwayswithout serious side effects due to drug actions outside the basalganglia (a serious problem for drugs such as glutamate antagonists). Itis important to emphasize that ambient adenosine levels and A_(2A)ARdensity are normal in PD patients,⁶¹ indicating that A_(2A) antagonistsmight remain effective, even in the later stages of PD.

The prospective use of A₂AR antagonists as potential neuroprotectiveagents against dopaminergic neuron degeneration was markedly enhanced bya May 2000 report of an epidemiological study of the relationshipbetween caffeine and PD. Ross et al described a large prospective studywith a 30-year follow-up of 8004 Japanese-American men that showed thatin this population there is an inverse relationship between caffeineconsumption and the risk of developing PD.⁶² Two other ongoing,large-cohort studies (Heath Professional Follow-up Studies and Nurse'sHeath Study) involving 47,351 men and 88,565 women also showed thatmoderate caffeine consumption (3–5 cups/day) reduced their risk ofdeveloping PD.⁶³ Thus, the inverse relationship of caffeine consumptionand the risk of developing PD seem firmly established by these twolarge, prospective epidemiological studies. These results are consistentwith the animal studies showing neuroprotection by A_(2A)AR antagonistsand strongly argue that A_(2A) antagonists including caffeine may offeran opportunity to slow down or halt the degeneration of dopaminergicneurons.

Initial clinical trial results of KW6002 indicated that (20–80 mg/day)enhanced motor activity in one study and potentiated a motor stimulanteffect by low (but not high) doses of L-dopa in another study.^(64,65)KW6002 was well tolerated and had few side effects. Unfortunately,trials with KW6002 have been stopped because this compound was found toproduce a long-term toxicity in rats. Hence, there is a pressing need todevelop alternative molecules that lack toxicity.

The first relatively selective A_(2A)AR antagonists, the8-styrylxanthines, appeared about ten years ago. This class includesKW-6002, which has low nanomolar affinity for the A_(2A)AR and >100-foldselectivity for the A_(2A)AR over the A₁AR. KW-6002, entered clinicaltrials in 2002 as an agent for the treatment of PD.^(1,66) SCH58261, apyrazolo[4,3-e]-1,2,4triazolo[1,5-c]pyrimidine was a prototype for aseries of second-generation derivatives that appeared over the nextseveral years. These, too, had low nanomolar affinity and goodselectivity for the A_(2A)AR in vitro.⁶⁷ The third class of antagoniststo appear, the 1,2,4-triazolo[4,5-e]-1,3,5-triazines, was typified byZM241385, which was active at the A_(2A)AR in the sub-nanomolar rangebut less selective, interacting with A_(2B)AR as well.⁶⁸ These potentA_(2A) antagonists have been important research tools, greatlyfacilitating pharmacological investigations of A_(2A)AR function invitro as well as in vivo significantly enhancing our understanding ofthe neurobiology of the A_(2A)AR. However, each of these antagonists hasimportant drawbacks. KW-6002 is light-sensitive, undergoingphotoisomerization from the active E-isomer to the 800-fold less activeZ-isomer.⁶⁹ SCH58261 is very poorly soluble and even itssecond-generation derivatives have marginal bioavailability.⁷⁰ Asmentioned above, ZM241385 is unselective and, additionally, has poorbioavailability. Other nitrogen heterocycles such as the1,2,4-triazolo[4,3-a]quinoxalin-1-ones⁷¹ and theoxazolo[4,5-d]pyrimidines from ICI are also unselective, and theirbioavailability is unknown. Therefore a continuing need exists forcompounds that are selective A_(2A) AR antagonists.

SUMMARY OF THE INVENTION

In one aspect, there is provided a compound of the formula I:

wherein R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe,—SMe, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R¹ and R² areoptionally substituted with 1 to 4 substituents of R^(a), wherein thealkyl is optionally interrupted by 1–4 heteroatoms selected from —O—,—S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R¹ and R² areindependently absent, with the proviso that R^(a) is not thio or halogenin the case where R¹ and R² to which R^(a) is bound is halogen, —NH₂,—OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe and —SMe; R³ is selected from the groupconsisting of hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(a) and —OPO₂R^(a); or if thering formed from the group CR³R⁴R⁵ is aryl or heteroaryl or partiallyunsaturated, then R³ can be absent; R⁴ and R⁵ together with the atoms towhich they are attached form a saturated or partially unsaturated,mono-, bi- or tricyclic- or aromatic ring having 3, 4, 5, 6, 7, 8, 9,10, 11 or 12 ring atoms, wherein the ring atoms are optionallyinterrupted by 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— or amine (—NR^(a)—) in the ring,wherein any ring comprising R⁴ and R⁵ is optionally further substitutedwith from 1 to 14 R⁶ groups; wherein each R⁶ is independently selectedfrom the group consisting of halo, —OR^(a), —SR^(a), substituted orunsubstituted (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₁–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl, heterocycle,hetrocyclyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(a) and —OPO₂R^(a) or two R⁶ groups and theatom to which they are attached combined to form C═O or C═S, or whereintwo R⁶ groups together with the atom or atoms to which they are attachedcan form a carbocyclic or heterocyclic ring; R⁷ and R⁸ are eachindependently hydrogen, (C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl oraryl(C₁–C₈)alkylene, heteroaryl, heteroaryl(C₁–C₈)alkylene-; or whereinR⁷ and R⁸ together with the nitrogen atom to which they attach form aheterocycle or heteroaromatic ring; R⁹ and R¹⁰ are each independentlyselected from the group consisting of hydrogen, halogen, —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OMe, —SMe, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl,wherein R⁹ and R¹⁰ are optionally substituted with 1 to 4 substituentsof R^(a), wherein the alkyl is optionally interrupted by 1 to 4heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—),or where R⁹ and R¹⁰ are independently absent, with the proviso thatR^(a) is not thio or halogen in the case where R⁹ and R¹⁰ to which R^(a)is bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe and —SMe; Yis —CR³R⁴R⁵ or NR⁴R⁵; Z is selected from the group consisting ofhydrogen, halogen, (C₁–C₈)alkyl, (C₁–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, (C₆–C₂₀)polycyclyl, heterocyclyl,cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heterocyclyl(C₁–C₈)alkyl, aryl, aryl(C₅–C₁₄), aryl(C₁–C₈)alkyl,heteroaryl, heteroaryl(C₁–C₈)alkyl, —NR^(a)R^(b), —OR^(a), —SR^(a),cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, —NNR^(a), —OPO₂R^(a),—OS(O₂)R^(a), —OS(═O)OR^(a), —OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b); R^(a)and R^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OMe, —SMe,propargyl, cyano, —NNH, —NNCH₃, —OPO₂H, —OPO₂CH₃, —OS(O₂)H, —OS(O₂)OH,—OS(O₂)CH₃, —OS(O₂)OCH₃, (C₁–C₈)alkyl, aryl, aryl(C₁–C₈alkyl,(C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl,bicycloalkyl(C₆–C₁₂)alkyl, heteroaryl and heteroaryl(C₁–C₈)alkyl,wherein the alkyl and cycloalkyl are optionally interrupted with 1–4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— and amino (—NR^(c)—); and wherein the alkyl, cycloalkyl, aryland heteroaryl are optionally substituted with 1, 2, 3 or 4 substituentsselected from the group consisting of —OR^(c), —NR^(c)R^(c), —SR^(c),cyano, —NNH, —NNCH₃, —OPO₂H, —OPO₂CH₃, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that R^(a) is not a heteroatom when it isattached to another heteroatom; R^(c) is selected from the groupconsisting of hydrogen and (C₁–C₈)alkyl; and m is 0 to 8; n is 0, 1, 2or 3, provided that when m is 0, Z is not halogen, cyano, nitro or aheteroatom, and when n is 0, Y is not —NR⁴R⁵; or a pharmaceuticallyacceptable salt thereof, optionally in the form of a single stereoisomeror mixture of stereoisomers thereof.

In another aspect, there is provided a compound of the formula II:

wherein R¹, R², R⁷, R⁸, R⁹, R¹⁰, m, n, Y and Z are as defined above; andL is a linker selected from the group consisting of —(C₁–C₃)alkyl-C≡C—,—C≡C—(C₁–C₃)alkyl-, —(CH₂)₁₋₃—CH═CH—, —CH═CH—CH₂)₁₋₃—,—(CH₂)₁₋₂—CH═CH—CH₂— and —CH₂—CH═CH—(CH₂)₁₋₂; or a pharmaceuticallyacceptable salt thereof, optionally in the form of a single stereoisomeror mixture of stereoisomers thereof.

In another aspect, there is provided a compound of the formula III:

wherein R¹, R², R⁷, R⁸, R⁹, R¹⁰, m, n, Y and Z are as defined above; andL is a linker selected from the group consisting of —NH—, —N═N—, —NH—N═,—O—, —S—, —SO₂— and pyrazolyl; a pharmaceutically acceptable saltthereof, optionally in the form of a single stereoisomer or mixture ofstereoisomers thereof.

In one variation of each of the above compound of formulae I, II andIII, the group (CR¹R²)_(m) together is selected from the groupconsisting of methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene, iso-propylene, iso-butylene, sec-butyleneand tert-butylene. In another variation, (CR¹R²)_(m) together isselected from the group consisting of methylene, ethylene, propylene andiso-propylene. In another variation, (CR¹R²)_(m))-Z together is selectedfrom the group consisting of —CH₂CH═CH₂—, —CH₂C≡CH, —CH₂C≡CCH₃ or—CH₂CH₂C≡CH. In yet another variation, (CR¹R²)_(m))-Z together is—CH₂C≡CH.

In another variation of the above formulae, R₁ and R₂ are hydrogen orare absent, m is 2 to 8 and the group (CR¹R²)_(m) optionally comprises 1to 4 alkenyl or alkynyl conjugated or unconjugated groups. In anothervariation, m is 1 to 8 and Z is selected from the group consisting of—NH₂, —OH, —SH, —NR^(a)R^(b), —OR^(a), —SR^(a) and cyano. In anotherparticular variation, (CR¹R²)_(m)-Z together is selected from the groupconsisting of methanol, ethanol, propanol, butanol, pentanol, hexanol,iso-propanol, iso-butanol, sec-butanol and tert-butanol. In yet anothervariation, (CR¹R²)_(m)-Z together is selected from the group consistingof methanol, ethanol, propanol and —CH₂CN.

In one variation of each of the above, R₁ and R² are hydrogen, and thegroup (CR¹R²)_(m) is linear or branched, m is 1 to 6, and Z is selectedfrom the group consisting of methoxy, ethoxy, propoxy, butoxy, pentoxyand hexyloxy. In another variation, Z is selected from the groupconsisting of methoxy, ethoxy and propoxy. In another variation, Z is amono-, bicyclic-, tricyclic- or aromatic or non-aromatic(C₃–C₂₀)cycloalkyl ring, wherein the ring atoms are optionallyinterrupted by 1 to 8 heteroatoms selected from the group consisting of—O—, —S—, —SO—, —S(O)₂— and amino (—NR^(a)—). In yet another variation,Z is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl ring optionallysubstituted with 1 to 4 substituents of R^(a). In yet another variation,Z is selected from the group consisting of cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl, where m is 0 or 1. In another variation, Zis cyclopentyl and where m is 0. In a particular variation, Z iscyclobutyl, m is 1 and R¹ and R² are hydrogen.

In one particular variation of each of the above; Y and Z are eachindependently selected from the group consisting of hydrogen, or

wherein each Y or Z group is optionally comprises 1, 2 or 3 doublebonds; each carbon in the ring is optionally replaced by or interruptedby 1 to 6 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂—, or amino(—NR^(a)—), and is optionally further substituted with from 1 to 10 R⁶groups, provided that the Y or Z ring is not attached at a bridgeheadcarbon atom or at a trisubstituted carbon atom. In another variation,each Y or Z is independently hydrogen or a bicyclic ring selected fromthe group consisting of

wherein any two adjacent carbon ring atom is optionally interrupted with1 to 6 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino(—NR^(a)—), and the ring is optionally substituted with from 1 to 7R^(a) groups selected from the group consisting of —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OMe, —SMe, propargyl, cyano, —NNH, —NNCH₃, —OPO₂H,—OPO₂CH₃, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃ and —OS(O₂)OCH₃, and m and nare each independently 0 or 1. In another variation, each Y or Z isindependently selected from the group consisting of hydrogen, or

wherein m and n are each independently 0 or 1, and R¹, R², R⁹ and R¹⁰are each independently absent or selected from the group consisting ofhydrogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂—OMe and —SMe, and each Zgroup is optionally substituted with from 1 to 7 R^(a) groups selectedfrom the group consisting of halo, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OMe, —SMe, propargyl, cyano, —NNH, —NNCH₃, —OPO₂H, —OPO₂CH₃, —S(SO₂)H,—S(SO₂)OH, —S(SO₂)CH₃ and —S(SO₂)OCH₃.

In another variation of the above, R¹ and R² are hydrogen, m is 0, 1, 2or 3 and Z is selected from the group consisting of furan,dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole,2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole,imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole,2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole,2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane,thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane,wherein each Z group is optionally substituted with from 1 to 10 R^(a)groups.

In yet another variation, R¹ and R² are hydrogen, m is 0 or 1, and Z isselected from the group consisting of furan, thiophene, pyrrole,2H-pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole,isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,1,2,4-triazole, 1,3,4-thiadiazole and 1H-tetrazole, wherein each Z groupis optionally substituted with from 1 to 3 R^(a) groups selected fromthe group consisting of methyl, ethyl, propyl, iso-propyl, —NH₂, —OH,—SH, —NHCH₃, —N(CH₃)₂, —OCH₃ and —SCH₃. In another variation, Z isselected from the group consisting of —CO₂R^(a), R^(a)C(═O)O—,R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)NR^(a)—,R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(O₂)—,—N═NR^(a), —OPO₂R^(a), —OS(O₂)R^(a), —OS(═O)OR^(a), —OS(O₂)OR^(a) and—OS(O₂)NR^(a)R^(b), wherein m is 1 to 8, and the group (CR¹R²)_(m) isoptionally saturated or partially unsaturated. In yet another variation,Z is selected from the group consisting of —CO₂R^(a), R^(a)C(═O)O—,R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)NR^(a)—,R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, —OPO₃R^(a),R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—,—N═NR^(a), —OPO₂R^(a), —OS(O₂)R^(a), —OS(═O)OR^(a), —OS(O₂)OR^(a) and—O(SO₂)NR^(a)R^(b), and wherein (R¹R²)_(m) together is selected from thegroup consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH═CHCH₂—, —CH₂CH═CH—,—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, —C≡CCH₂—, —CH₂C≡C—,—C≡CCH₂CH₂—, —CH₂C≡CCH₂— and —CH₂CH₂C≡C—. In still another variation ofthe above, Z is independently —CO₂R^(a), R^(a)C(═O)—, R^(a)R^(b)N—,—OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—, R^(a)S(═O)—, R^(a)S(═O)₂—,—OPO₂R^(a), —OS(O₂)R^(a), —OS(═O)OR^(a), —OS(O₂)OR^(a) or—OS(O₂)NR^(a)R^(b), and wherein (CR¹R²)_(m) together is selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH═CHCH₂—, —CH₂CH═CH—,—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, —C≡CCH₂—, —CH₂C≡C—,—C≡CCH₂CH₂—, —CH₂C≡CCH₂— and —CH₂CH₂C≡C—.

In one particular variation of each of the above; each R⁹ isindependently selected from the group consisting of hydrogen, halo,—OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocyclyl,hetrocyclyl(C₁–C₈)alkylene-, aryl, aryl(C₁–C₈)alkylene-, heteroaryl,heteroaryl(C₁–C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —N═NR^(a) and —OPO₂R^(a). Inanother variation, R¹ and R² together with the carbon atom to which theyare attached is C═O, C═S or C═NR^(c). In yet another variation, R³ isselected from the group consisting of hydrogen, halo, —OR^(a), —SR^(a),cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(a) and —OPO₂R^(a); or if thering formed from the group CR³R⁴R⁵ is aryl or heteroaryl or partiallyunsaturated then R³ can be absent. In another variation of the above, R³is selected from the group consisting of hydrogen, OH, OMe, OAc, NH₂,NHMe, NMe₂ and NHAc. In a particular variation, R³ is hydrogen or OH.

In one particular variation of each of the above; R⁴ and R⁵ togetherwith the atom to which they are attached form a saturated or partiallyunsaturated, mono-, bi- or tricyclic ring, or aromatic ring having 3, 4,5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein the ring atoms areoptionally interrupted by 1, 2, 3 or 4 heteroatoms selected from thegroup consisting of —O—, —S—, —SO—, —S(O)₂— or amine (—NR^(a)—) in thering, wherein any ring comprising R⁴ and R⁵ is optionally furthersubstituted with from 1 to 14 R⁶ groups; wherein each R⁶ isindependently selected from the group consisting of halo, —OR^(a),—SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₁–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl, heterocycle,hetrocyclyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(a), —OPO₂R^(a), or two R⁶ groups and theatom to which they are attached combined to form C═O or C═S, or whereintwo R⁶ groups together with the atom or atoms to which they are attachedcan form a carbocyclic or heterocyclic ring. In another variation, thering comprising R⁴ and R⁵ and the atom to which they are attached isselected from the group consisting of cyclopentane, cyclohexane,piperidine, dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine,decaline, tetrahydro-pyrazine, dihydro-pyrazine, pyrazine,dihydro-pyrimidine, tetrahydro-pyrimidine, hexahydro-pyrimidine,pyrazine, imidazole, dihydro-imidazole, imidazolidine, pyrazole,dihydro-pyrazole, pyrazolidine, norbornane and adamantane, eachunsubstituted or substituted.

In one particular variation of each of the above, R⁶ is selected fromthe group consisting of substituted or unsubstituted (C₁–C₈)alkyl,—OR^(a), —CO₂R^(a), R^(a)C(═O)—, R^(a)C(═O)O—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)— and aryl, provided that when the ring comprising R⁴and R⁵ contains a heteroatom that is O or S, the heteroatom is notsubstituted with R⁶. In another variation, R⁶ is selected from the groupconsisting of OH, OMe, methyl, ethyl, t-butyl, —CO₂R^(a),—CONR^(a)R^(b), OAc, NH₂, NHMe, NMe₂, NHEt and N(Et)₂, provided thatwhen the ring comprising R⁴ and R⁵ contains a heteroatom that is O or S,the heteroatom is not substituted with R⁶. In yet another variation, R⁶is selected from the group consisting of methyl, ethyl, —CO₂R^(a),—CONR^(a)R^(b) and OAc, provided that when the ring comprising R⁴ and R⁵contains a heteroatom, the heteroatom is not substituted with OAc. Inyet another variation, R⁶ is selected from the group consisting of—(CH₂)₁₋₂OR^(a), —(CH₂)₁₋₂C(═O)OR^(a), —(CH₂)₁₋₂OC(═O)R^(a),—(CH₂)₁₋₂C(═O)R^(a), —(CH₂)₁₋₂OCO₂R^(a), —(CH₂)₁₋₂NHR^(a),—(CH₂)₁₋₂NR^(a)R^(b), —(CH₂)₁₋₂OC(═O)NHR^(a) and—(CH₂)₁₋₂OC(═O)NR^(a)R^(b). In yet another variation, R⁶ is—CH₂C(═O)OR^(a), —CH₂OC(═O)OR^(a), —CH₂OH, —CH₂OAc, —CH₂NH(CH₃) and—(CH₂)₁₋₂N(CH₃)₂. In another variation, the number of R₆ groupssubstituted on the R₄R₅ ring is from 1 to 4.

In another variation, R⁷ and R⁸ is selected from the group consisting ofhydrogen, (C₁–C₈)alkyl-, aryl, aryl(C₁–C₈)alkylene-, mono-, bicyclic- oraromatic or nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10 ringatoms, wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, and each is optionallysubstituted with from 1, 2, 3 or 4 R^(a) groups. In yet anothervariation, R⁷ is selected from the group consisting of hydrogen, methyl,ethyl, propyl, butyl,3-pentyl, iso-propyl, iso-butyl, sec-butyl,tert-butyl, phenyl and benzyl, or wherein R⁷ is hydrogen, methyl orsec-butyl. In another variation, R⁷ and R⁸ are each independentlyselected from the group consisting of hydrogen, (C₁–C₈)alkyl,(C₃–C₈)cycloalkyl, aryl, aryl(C₁–C₈)alkylene, heteroaryl andheteroaryl(C₁–C₈)alkylene-; or wherein R⁷ and R⁸ together with thenitrogen atom to which they attach form a heterocycle or heteroaromaticring.

In one particular variation of each of the above, —NR⁷R⁸ is selectedfrom the group consisting of amino, methylamino, dimethylamino,ethylamino, pentylamino, diphenylethylamino, pyridylmethylamino,diethylamino and benzylamino. In another variation, —NR⁷R⁸ is selectedfrom the group consisting of amino, methylamino, dimethylamino,ethylamino, diethylamino and benzylamino, or wherein —NR⁷R⁸ is amino.

In one particular variation of each of the above; R^(a) and R^(b) areeach independently selected from the group consisting of hydrogen,(C₁–C₈)alkyl and (C₁–C₈)alkyl substituted with 1 to 3 (C₁–C₈)alkoxy,(C₃–C₈)cycloalkyl, (C₁–C₈)alkylthio, aryl, aryl(C₁–C₈)alkylene,heteroaryl, or heteroaryl(C₁–C₈)alkylene; or R^(a) and R^(b) togetherwith the nitrogen to which they are attached, form a pyrrolidino,piperidino, morpholino, or thiomorpholino ring; R^(c) is hydrogen or(C₁–C₆)alkyl; m is 0 to about 8 and p is 0 to 2; and Y is —CR³R⁴R⁵ orNR⁴R⁵.

In another variation, R⁷ is selected from the group consisting ofbenzyl, phenethyl, phenylpropyl and each is optionally substituted withfrom 1, 2 or 3 substituents of R^(a). In a particular variation, R⁷ isselected from the group consisting of benzyl, phenethyl, phenylpropyland each is optionally substituted with from 1, 2 or 3 substituents ofR^(a) selected from the group consisting of methyl, ethyl, propyl,methoxy, ethoxy and propoxy; or wherein R⁷ is benzyl and R^(a) ismethoxy.

In another aspect of the above, R⁹ is selected from the group consistingof hydrogen, fluoro, —OH, —CH₂OH, —OMe, —OAc, —NH₂, —NHMe, —NMe₂ and—NHAc; or wherein R⁹ is hydrogen or OH. In one variation, each R¹⁰ isindependently selected from the group consisting of hydrogen, fluoro,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, heterocyclyl,heterocycle(C₁–C₈)alkylene-, aryl, aryl(C₁–C₈)alkylene-, heteroaryl andheteroaryl(C₁–C₈)alkylene-. In another variation, R¹⁰ is selected fromthe group consisting of hydrogen, (C₁–C₈)alkyl, cyclopropyl, cyclohexyland benzyl; or wherein R¹⁰ is hydrogen. In yet another variation of theabove, R⁹ and R¹⁰ and the carbon atom to which they are attached is aC═O group.

In a variation of the above compound, R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen,(C₁–C₄)alkyl, aryl and aryl(C₁–C₈)alkylene. In a particular variation,R^(a) and R^(b) are each independently selected from the groupconsisting of hydrogen, methyl, ethyl, phenyl and benzyl. In anothervariation, R^(a) is (C₁–C₈)alkyl. In yet another variation, R^(a) isselected from the group consisting of methyl, ethyl, propyl and butyl.In yet another variation, R^(a) is selected from the group consisting ofmethyl, ethyl, i-propyl, i-butyl and tert-butyl. In still anothervariation, R^(a) and R^(b) is a ring.

In one variation of each of the above, Y is —CR₃R₄R₅ or NR₄R₅, and isselected from the group consisting of:

wherein q is 0, 1, 2, 3 or 4; R³ is selected from the group consistingof hydrogen, halo, —OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(a) and —OPO₂R^(a); and eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₁–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(a) and —OPO₂R^(a), provided that R⁶ is nothalogen or a heteroatom when R⁶ is attached to a heteroatom.

In another variation, Y is —CR³R⁴R⁵ or NR⁴R⁵ and is selected from thegroup consisting of:

wherein R³ is selected from the group consisting of hydrogen, halo,—OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —NNR^(a) and —OPO₂R^(a); and eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₁–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, —OPO₃R^(a), R^(a)OC(═S)—, R^(a)C(═S)—,—SSR^(a), R^(a)S(═O)—, —NNR^(a) and —OPO₂R^(a).

In another variation, the ring comprising —C(R³)R⁴R⁵ is2-methylcyclohexan-1-yl, 2,2-dimethylcyclohexan-1-yl,2-ethylcyclohexan-1-yl, 2,2-diethylcyclohexan-1-yl,2-tert-butylcyclohexan-1-yl, 2-phenylcyclohexan-1-yl,3-methylcyclohexan-1-yl, 3-ethylcyclohexan-1-yl,3,3-dimethylcyclohexan-1-yl, 4-methylcyclohexan-1-yl,4-ethylcyclohexan-1-yl, 4,4-dimethylcyclohexan-1-yl,4-tert-butylcyclohexan-1-yl, 4-phenylcyclohexan-1-yl,3,3,5,5-tetramethylcyclohexan-1-yl, 2,4-dimethylcyclopentan-1-yl,4-(carboxyl)cyclohexan-1-yl, 4-(carboxymethyl)cyclohexan-1-yl and4-(carboxyethyl)cyclohexan-1-yl. In yet another variation, the ringcomprises —(R³)R⁴R⁵ is piperidin-4-yl, 1-carboxypiperiden-4-yl,1-(methoxycarbonyl)piperidin-4-yl, 1-(ethoxycarbonyl)piperidin-4-yl,1-(n-propoxycarbonyl)piperidin-4-yl,1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,4-carboxypiperiden-1-yl, 4-(methoxycarbonyl)piperidine-1-yl,4-(ethoxycarbonyl)piperidine-1-yl, 4-(n-propoxy)piperidine-1-yl,4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,1-carboxypiperidene-3-yl, 1-(methoxycarbonyl)piperidine-3-yl,1-(ethoxycarbonyl)piperidine-3-yl, 1-(n-propoxycarbonyl)piperidine-3-yl,1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,3-carboxypiperidene-1-yl, 3-(methoxycarbonyl)piperidine-1-yl,3-(ethoxycarbonyl)piperidine-1-yl, 3-(n-propoxycarbonyl)piperidine-1-yl,3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperazin-1-yl,1-caboxypiperazin-4-yl, 1-(methoxycarbonyl)piperazin-4-yl,1-(ethoxycarbonyl)piperazin-4-yl and1-(n-propoxycarbonyl)piperazin-4-yl.

In another variation, the ring comprising —C(R³)R⁴R⁵ is selected fromthe group consisting of 2-methylcyclohexan-1-yl,2,2-dimethylcyclohexan-1-yl, 2-ethylcyclohexan-1-yl,2,2-diethylcyclohexan-1-yl, 2-tert-butylcyclohexan-1-yl,2-phenylcyclohexan-1-yl, 3-methylcyclohexan-1-yl,3-ethylcyclohexan-1-yl, 3,3-dimethylcyclohexan-1-yl,4-methylcyclohexan-1-yl, 4-ethylcyclohexan-1-yl,4,4-dimethylcyclohexan-1-yl, 4-tert-butylcyclohexan-1-yl,4-phenylcyclohexan-1-yl, 3,3,5,5-tetramethylcyclohexan-1-yl,2,4-dimethylcyclopentan-1-yl, 4-(carboxyl)cyclohexan-1-yl,4-(carboxymethyl)cyclohexan-1-yl, 4-(carboxyethyl)cyclohexan-1-yl,piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,4-(methoxycarbonyl)piperidine-1-yl,4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,1-(methoxycarbonyl)piperidine-3-yl,1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,3-(methoxycarbonyl)piperidine-1-yl and3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl.

In a particular variation, Z is a mono-, bicyclic-, tricyclic- oraromatic or non-aromatic (C₃–C₂₀)cycloalkyl ring, wherein the ring atomsare optionally interrupted by 1–8 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(a)—). In onevariation of the above, R¹ and R² are hydrogen, m is 0, 1, 2 or 3 and Zis selected from the group consisting of furan, dihydro-furan,tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline,3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole,dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline,pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole,2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane,thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane,wherein each Z group is optionally substituted with from 1 to 10 R^(a)groups. In another variation, Z is a mono-, bicyclic—, tricyclic- oraromatic or non-aromatic (C₃–C₂₀)cycloalkyl ring, wherein the ring atomsare optionally interrupted by 1–8 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(a)—).

In a particular variation, R¹ and R² are hydrogen, m is 0, 1, 2 or 3 andZ is selected from the group consisting of furan, dihydro-furan,tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline,3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole,dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline,pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole,2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane,thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane,wherein each Z group is optionally substituted with from 1 to 10 R^(a)groups.

In another aspect, there is provided a compound of the formula:

wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, (C₂–C₄)alkyl, 3-pentyl, aryl(C₂–C₄)alkyl,heteroaryl(C₂–C₄)alkyl, each unsubstituted or substituted, R⁸ isselected from the group consisting of hydrogen or (C₁–C₄)alkyl; and R¹¹is selected from the group consisting of (C₁–C₄)alkyl, propargyl,(C₃–C₆)cycloalkyl, (C₃–C₆)cycloalkyl(C₁–C₄)alkyl, aryl(C₁–C₄)alkyl,heteroaryl(C₁–C₄)alkyl, heterocyclyl(C₁–C₄)alkyl, HO(C₁–C₄)alkyl,halo(C₁–C₄)alkyl, —COO(C₁–C₄)alkyl, (C₁–C₄)alkylCOO(C₁–C₄)alkyl, eachunsubstituted or substituted; R¹³ is methyl, iso-propyl, iso-butyl, ortert-butyl; and R¹, R² and m are as defined herein; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.

In another aspect, there is provided a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of each ofthe above, and a pharmaceutically acceptable excipient. Some of thecompounds of formulae I, II, and III may further form pharmaceuticallyacceptable salts and esters. All of these forms are included within thescope of the present invention. Pharmaceutically acceptable baseaddition salts of the compounds of formulae I, II, and III include saltswhich may be formed when acidic protons present in the parent compoundare capable of reacting with inorganic or organic bases as known in theart. Acceptable inorganic bases, include for example, aluminumhydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate andsodium-hydroxide. Salts may also be prepared using organic bases, suchas choline, dicyclohexylamine, ethylenediamine, ethanolamine,diethanolamine, triethanolamine, procaine, N-methylglucamine, and thelike [see, for example, Berge et al., “Pharmaceutical Salts,” J. Pharma.Sci. 66:1 (1977)]. Pharmaceutically acceptable acid addition salts ofthe compounds of formulae I, II, and III include salts which may beformed when the parent compound contains a basic group. Acid additionsalts of the compounds may be prepared in a suitable solvent from theparent compound and an excess of a non-toxic inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid (giving the sulfateand bisulfate salts), nitric acid, phosphoric acid and the like, or anon-toxic organic acid such as aceticacid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, camphorsulfonic acid, tert-butylacetic acid, laurylsulfuric acid,glucuronic acid, glutamic acid, and the like. The free base form may beregenerated by contacting the acid addition salt with a base andisolating the free base in the conventional manner. The free base formscan differ from their respective salt forms somewhat in certain physicalproperties such as solubility in polar solvents.

Also included in the above embodiments, aspects and variations are saltsof amino acids such as arginate and the like, gluconate, andgalacturonate. Some of the compounds of the invention may form innersalts or Zwitterions. Certain of the compounds of the present inventioncan exist in unsolvated forms as well as solvated forms, includinghydrated forms, and are intended to be within the scope of the presentinvention. Certain of the above compounds may also exist in one or moresolid or crystalline phases or polymorphs, the variable biologicalactivities of such polymorphs or mixtures of such polymorphs are alsoincluded in the scope of this invention. Also provided arepharmaceutical compositions comprising pharmaceutically acceptableexcipients and a therapeutically effective amount of at least onecompound of this invention.

Pharmaceutical compositions of the compounds of this invention, orderivatives thereof, may be formulated as solutions or lyophilizedpowders for parenteral administration. Powders may be reconstituted byaddition of a suitable diluent or other pharmaceutically acceptablecarrier prior to use. The liquid formulation is generally a buffered,isotonic, aqueous solution. Examples of suitable diluents are normalisotonic saline solution, 5% dextrose in water or buffered sodium orammonium acetate solution. Such formulations are especially suitable forparenteral administration but may also be used for oral administration.Excipients, such as polyvinylpyrrolidinone, gelatin, hydroxycellulose,acacia, polyethylene glycol, mannitol, sodium chloride, or sodiumcitrate, may also be added. Alternatively, these compounds may beencapsulated, tableted, or prepared in an emulsion or syrup for oraladministration. Pharmaceutically acceptable solid or liquid carriers maybe added to enhance or stabilize the composition, or to facilitatepreparation of the composition. Liquid carriers include syrup, peanutoil, olive oil, glycerin, saline, alcohols, or water. Solid carriersinclude starch, lactose, calcium sulfate, dihydrate, terra alba,magnesium stearate or stearic acid, talc, pectin, acacia, agar, orgelatin. The carrier may also include a sustained release material suchas glyceryl monostearate or glyceryl distearate, alone or with a wax.The amount of solid carrier varies but, preferably, will be betweenabout 20 mg to about 1 g per dosage unit. The pharmaceuticalpreparations are made following the conventional techniques of pharmacyinvolving milling, mixing, granulation, and compressing, when necessary,for tablet forms; or milling, mixing, and filling for hard gelatincapsule forms. When a liquid carrier is used, the preparation will be inthe form of a syrup, elixir, emulsion, or an aqueous or non-aqueoussuspension. Such a liquid formulation may be administered directly p.o.or filled into a soft gelatin capsule. Suitable formulations for each ofthese methods of administration may be found in, for example, Remington:The Science and Practice of Pharmacy, A. Gennaro, ed., 20th edition,Lippincott, Williams & Wilkins, Philadelphia, Pa.

In one variation, there is provided the above compound, or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof. In one aspect,there is provided a method for stimulating motor activity withoutdyskinesia in a mammal, comprising administering a therapeuticallyeffective amount of an A_(2A) anatagonist compound of the above to themammal in need of such treatment. In one variation of the above method,the therapeutically effective amount is effective to treat ischemia,brain damage induced by ischemia and excitoxicity, Huntington disease,catalepsy, cancer, drug addiction and withdrawal, Parkinson's disease(drug induced, post-encephalitic, poison induced or post-traumaticinduced), acute or chronic pain, narcolepsy and Alzheimer's disease. Inanother variation of the above, the therapeutically effective amount iseffective to stimulate motor activity for treating a movement disorder,where the disorder is progressive supernuclear palsy, Huntington'sdisease, multiple system atrophy, corticobasal degeneration, Wilsonsdisease, Hallerrorden-Spatz disease, progressive pallidal atrophy,Dopa-responsive dystonia-Parkinsonism, spasticity or other disoders ofthe basal ganglia which result in dyskinesias. In another variation ofthe above, the compound is used in combination with one or moreadditional drugs in the treatment of movement disorders (i.e. L-DOPA ordopamine agonist), addiction, or cancer with the components being in thesame formulation or in a separate formulation for administrationsimultaneously or sequentially. In yet another variation of the method,the therapeutically effective amount is effective to provideneuroprotection and slow or halt the degeneration of dopaminergicneurons. In yet another variation, the therapeutically effective amountis effective to enhance the immune response by increasing the activityof an immune cell in a mammal. In one variation, the activity ispro-inflammatory cytokine production. In another variation, the activityof the immune cell results in an increase in inflammation. In yetanother variation of the above method, the mammal is human.

In another embodiment of the invention, there is provided a method forstimulating motor activity without dyskinesia in a mammal, comprisingadministering a therapeutically effective amount of an A_(2A) antagonistcompound of the above to the mammal in need of such treatment. In onevariation of the above embodiment, there is provided a method asdescribed above wherein the A_(2A) antagonist is selected from acompound of each of the above embodiments, aspects and variations.

In another embodiment, there is provided a method to evaluate novelA_(2A) antagonists in four mouse models of PD. These include: A) motorfunction in normal and dopamine-depleted mice; B) synergistic activitywith L-dopa to stimulate motor activity in dopamine-depleted mice; C)attenuation MPTP-induced neurotoxicity by inhibiting MPTP metabolism;and D) delayed L-dopa-induced locomotor sensitization in unilateral6-OHDA-lesioned mice.

In another embodiment, there is provided a method comprising contactinga compound of each of the above formula with an isotope such as thosefrom hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine,chlorine, or iodine (e.g. ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³¹P, ³²P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I, ¹²⁵I) optionally being a radioactive isotope(radionuclide), such as, for example, tritium, radioactive iodine (forexample, ¹²⁵I for binding assays or ¹²³I for Spect Imaging) or othernon-radioactive isotope (such as deuterium) and the like. Isotopicallylabeled compounds may be useful for drug/tissue distribution assaysand/or manipulating oxidative metabolism via the primary kinetic isotopeeffect. They are also valuable in identifying potential therapeuticagents for the treatment of diseases or conditions associated withtarget-receptor mediation, by contacting said agents with saidradioligands and receptors, and measuring the extent of displacement ofthe radioligand and/or binding of the agent. Representative referencesfor Deuterium-for hydrogen substitution include Hanzlik et al., J. Org.Chem. 55, 3992–3997, 1990; Reider et al., J. Org. Chem. 52, 3326–3334,1987; Foster, Adv. Drug Res. 14 1–40, 1985; Gillette et al.,Biochemistry 33(10)2927–2937, 1994; and Jarman et al. Carcinogenesis16(4) 683–688, 1993, the references of which are incorporated herein intheir entirety. The use of radiolabelled compounds that may be detectedusing imaging techniques, such as, for instance, Single Photon EmissionComputerized Tomography (SPECT) or Positron Emission Tomography (PET)and the like, are known in the art. See for example, U.S. Pat. Nos.6,395,742; 6,472,667 and references cited therein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows locomotor stimulant activity of A_(2A)AR antagonistsinjected into mice.

FIG. 2 shows the effect of A_(2A)AR gene deletion on locomotor effect ofATL-2.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless specifically noted otherwise herein, the definition of the termsused are standard definitions used in the art of organic synthesis andpharmaceutical sciences.

Where a carbonyl group or a carbonyl derivative such as a thio carbonylor an imine and the like, is represented by a group such as —C(═O)O— or—C(═O)NR^(a)—, for example, it is intended that the correspondingisomeric group that is —OC(═O)— or —NR^(a)C(═O)— is also included.

An “alkyl” group is a straight, branched, saturated or unsaturated,aliphatic group having a chain of carbon atoms, optionally with oxygen,nitrogen or sulfur atoms inserted between the carbon atoms in the chainor as indicated. A (C₁–C₂₀)alkyl, for example, includes alkyl groupsthat have a chain of between 1 and 20 carbon atoms, and include, forexample, the groups methyl, ethyl, propyl, isopropyl, vinyl, allyl,1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,1,3-butadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl,hexa-1,3,5-trienyl, and the like. An alkyl group may also berepresented, for example, as a —(CR¹R²)_(m)— group where R¹ and R² areindependently hydrogen or are independently absent, and for example, mis 1 to 8, and such representation is also intended to cover bothsaturated and unsaturated alkyl groups. An alkyl as noted with anothergroup such as an aryl group, represented as “arylalkyl” for example, isintended to be a straight, branched, saturated or unsaturated aliphaticdivalent group with the number of atoms indicated in the alkyl group (asin (C₁–C₂₀)alkyl, for example) and/or aryl group (as in (C₅–C₁₄)aryl,for example) or when no atoms are indicated means a bond between thearyl and the alkyl group. Nonexclusive examples of such group includebenzyl, phenethyl and the like.

An “alkylene” group is a straight, branched, saturated or unsaturatedaliphatic divalent group with the number of atoms indicated in the alkylgroup (as in —(C₁–C₂₀)alkylene- or —(C₁–C₂₀)alkylenyl-, for example),optionally with one or more oxygen, nitrogen or sulfur atoms inserted(or “interrupted”) between the carbon atoms in the chain or asindicated.

A “cyclyl” such as a monocyclyl or polycyclyl group includes monocyclic,or linearly fused, angularly fused or bridged polycycloalkyl, orcombinations thereof. Such cyclyl group is intended to include theheterocyclyl analogs. A cyclyl group may be saturated, particallysaturated or aromatic.

“Halogen” or “halo” means fluorine, chlorine, bromine or iodine.

A “heterocyclyl” or “heterocycle” is a cycloalkyl wherein one or more ofthe atoms forming the ring is a heteroatom that is a N, O, or S.Non-exclusive examples of heterocyclyl include piperidyl, 4-morpholyl,4-piperazinyl, pyrrolidinyl, 1,4-diazaperhydroepinyl, 1,3-dioxanyl, andthe like.

“Pharmaceutically acceptable salts” means salt compositions that isgenerally considered to have the desired pharmacological activity, isconsidered to be safe, non-toxic and is acceptable for veterinary andhuman pharmaceutical applications. Such salts include acid additionsalts formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, and the like; or with organicacids such as acetic acid, propionic acid, hexanoic acid, malonic acid,succinic acid, malic acid, citric acid, gluconic acid, salicylic acidand the like.

“Substituted or unsubstituted” means that a group such as, for example,alkyl, aryl, heterocyclyl, (C₁–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,hetrocyclyl(C₁–C₈)alkyl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, the mono-, bi- or polycyclic rings that definethe Z group, and the like, unless specifically noted otherwise, may beunsubstituted or, may substituted by 1, 2, 3, 4 or 5 substitutentsselected from the group such as halo, nitro, trifluoromethyl,trifluoromethoxy, methoxy, carboxy, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—SMe, propargyl, cyano, —NNH, —NNCH₃, —OPO₂H, —OPO₂CH₃, —S(SO₂)H,—S(SO₂)OH, —S(SO₂)CH₃ and —S(SO₂)OCH₃, and the like.

Representative A_(2A)AR Antagonists

TABLE 1 Binding Affinity and Selectivity of A_(2A)AR Ligands^(a)

Ki, nM ATL # R¹² R⁷ (CR¹R²)_(m)-Z A₁AR A_(2A)AR A_(2B)AR A₃ARAntagonists 11 A 3-P Me  172 (1.3) 137 20% 30% 17 A 3-P Proparg  11 (2) 5 147 (29)  188 (38) 2 A NH₂ Proparg   4.6 (5)  0.95  50 (11)  599(630) 3 A NH₂ cPent  368 (37)  10 357 (36)  633 (63) 51 B NH₂ Proparg 25 (16)  1.6 155 (97) >650 (>400) 50 B NH₂ cPent >325 (>27)  12 40% 40%^(a)Abbreviations: 3-P, 3-pentyl; Me, methyl; Proparg, prop-2-ynyl;cPent, cyclopentyl. Numbers in parentheses are selectivity ratios vs.the A_(2A)AR. Activities expressed as percentage are displacement ofradioligand by 1 μM candidate ligand.Motor Enhancement by the Lipophilic A_(2A) Receptor Antagonist ATL-2 inNormal Mice

The ability of compounds to stimulate motor activity in normal mice wasmeasured using a simple, computer-assisted locomotor activity cagesystem. C57BL/6 mice (n═6–8 purchased from the Jackson's lab) werehabituated for the testing environment for 120 minute prior to drugtreatment. The test compounds were dissolved in vehicle (10% DMSO, 10%castrol oil EL-620 and 80% saline). The drug was administratedintraperitoneally at a dose of 15 mg/kg, and locomotor activity wasrecorded for 2 hours before and after drug administration.

FIG. 1 shows that ATL-2 produced strong motor stimulation, reaching peakwithin 20 minutes and lasting for about 60 minutes (arrow marks theinjection). From our previous experience with other A_(2A)R antagonists,the motor stimulant effect of ATL2 is comparable or stronger than otherA_(2A)R antagonists such as SCH58261 and KW6002.

Absence of Motor Stimulant Effect of ATL-2 in Mice Lacking the A_(2A)Receptor

We validated that ATL-2 acts on the A_(2A) receptor to stimulate motoractivity by using A₂AR KO mice (in both mixed (129sv X C57BL/6) as wellas congenic (C57BL/6 genetic background) developed over the last severalyears. We evaluated the motor stimulant effect of ATL-2 in A_(2A)receptor KO and their WT littermates. WT and A_(2A) KO mice (n=4) werehabituated for 60 minutes and treated with ATL-2 (15 mg/kg) and recordedfor motor activity for 120 minutes.

FIG. 2 shows that ATL-2 produced motor activity in WT mice (relativelyhigh basal locomotion is likely due to short habituation time (60 minuteinstead of 120 minutes) and demonstrates relatively higher basallocomotion in WT compared to KO mice as we noted previously,³⁵ but thismotor stimulation was absent in A_(2A) receptor KO mice.

Experimental

Synthesis of A_(2A)AR Antagonists

The following procedures may be employed for the preparation of thecompounds of the present invention. The starting materials and reagentsused in preparing these compounds are either available from commercialsuppliers such as the Aldrich Chemical Company (Milwaukee, Wis.), Bachem(Torrance, Calif.), Sigma (St. Louis, Mo.), or are prepared by methodswell known to a person of ordinary skill in the art, followingprocedures described in such references as Fieser and Fieser's Reagentsfor Organic Synthesis, vols. 1–17, John Wiley and Sons, New York, N.Y.,1991; Rodd's Chemistry of Carbon Compounds, vols. 1–5 and supps.,Elsevier Science Publishers, 1989; Organic Reactions, vols. 1–40, JohnWiley and Sons, New York, N.Y., 1991; March J.: Advanced OrganicChemistry, 4th ed., John Wiley and Sons, New York, N.Y.; and Larock:Comprehensive Organic Transformations, VCH Publishers, New York, 1989.In some cases, protective groups may be introduced and finally removed.Suitable protective groups for amino, hydroxy, and carboxy groups aredescribed in Greene et al., Protective Groups in Organic Synthesis,Second Edition, John Wiley and Sons, New York, 1991. Standard organicchemical reactions can be achieved by using a number of differentreagents, for examples, as described in Larock: Comprehensive OrganicTransformations, VCH Publishers, New York, 1989.

In one variation, the compounds of this invention can be synthesized bythe steps outlined in Scheme 1. Guanosine, A′, is acetylated to protectthe ribose during reductive chlorination by POCl₃/diethylaniline to form6-chloroguanosine, C′. Non-aqueous diazotization in the presence ofelemental iodine in diiodomethane is a standard route to the protected6-chloro-2-iodonebularine, D′. Heating in methanolic ammonia deprotectsthe sugar and displaces the 6-chloro substituent to form2-iodoadenosine, E′. Palladium-catalyzed coupling of E′ with a terminalalkyne generates 2-alkynyladenosine F′, which undergoes acid hydrolysisto form 9H-adenine G′. Alkylation with an appropriate halide (alkyl,cycloalkyl or heterocyclic) completes the synthesis of target2,9-disubstituted adenine H′.

Preparation of the terminal alkynes(S)-1-ethynyl-1-hydroxy-(R)-3-methylcyclohexane and2-ethynyladamantan-2-ol is achieved by treatment of the correspondingketone with ethynylmagnesium bromide.

Preparation of the substituted piperidine-carboxylate terminal alkynes(Scheme 2) starts with 4-carboxypiperidine (isonipecotic acid) I′ inanticipation of acylating the methyl ester, J′, with the appropriatealkyl chloroformate to form the N-carbamoyl ester K′. Borohydridereduction of the ester generates the 4-hydroxymethylpiperidine, L′,which undergoes tosylation to M′ in preparation for condensation withlithium acetylide to form terminal alkyne N′.

Compound No. R⁷ R⁸ (CR¹R²)_(m)-Z Human K_(i) (nM) 1 H H

++++ 2 H H Propargyl ++++ 3 H H Cyclopentyl ++++ 4 H H —CH₂CN ++++ 5 H H4-Methoxybenzyl 6 H H 3,4-Dichlorobenzyl 7 H H 4-(Trifluoromethyl)benzyl 8 H H

++++ 9 H H

10 H H

+++ 11 Pent-3-yl H —CH₃ +++ 12 Pent-3-yl H —CH₂CH₂CH₃ ++++ 13 Pent-3-ylH Iso-propyl +++ 14 Pent-3-yl H

++++ 15 Pent-3-yl H Cyclopentyl ++++ 16 Pent-3-yl H Allyl ++++ 17Pent-3-yl H Propargyl ++++ 18 Pent-3-yl H —(CH₂)₃C≡CH ++++ 19 Pent-3-ylH —CH₂CH₂OH ++++ 20 Pent-3-yl H —CH₂CH₂CH₂OH +++ 21 Pent-3-yl H—CH₂CH₂Cl 22 Pent-3-yl H

+++ 23 Pent-3-yl H

24 Pent-3-yl H

25 Pent-3-yl H

+++ 26 Pent-3-yl H

27 Pent-3-yl H Benzyl ++++ 28 Pent-3-yl H

++++ 29 Pent-3-yl H 4-Nitrobenzyl 30 Pent-3-yl H

++++ 31 Pent-3-yl H

32

H Propargyl ++++ 33

H

++++ 34

H —CH₃ +++ 35

H Propargyl +++ 36 3-Methoxybenzyl H Propargyl ++++ 37

H Propargyl ++++ 38

—CH₃ Propargyl + K_(i) < 10,000 nM; ++ K_(i) < 1,000 nM; +++ K_(i) < 500nM; ++++ K_(i) < 100 nM.

Compound No. R⁷ (CR¹R²)_(m)-Z Human K_(i) (nM) 39 H —CH₃ ++++ 40 H—CH₂CH₃ ++++ 41 H —CH₂CH₂CH₃ ++++ 42 H —(CH₂)₅CH₃ ++ 43 H —(CH₂)₈CH₃ 44H Iso-propyl +++ 45 H

++++ 46 H

++++ 47 H

+++ 48 H

49 H Cyclobutyl ++++ 50 H Cyclopentyl ++++ 51 H Propargyl ++++ 52 H—CH₂CH₂OH +++ 53 H —CH₂CH₂CH₂OH +++ 62 H But-3-ynyl ++++ + K_(i) <10,000 nM; ++ K_(i) < 1,000 nM; +++ K_(i) < 500 nM; ++++ K_(i) < 100 nM.

Compound No. (CR⁹R¹⁰)_(n)—Y (CR¹R²)_(m)-Z Human K_(i) (nM) 60

Propargyl ++++ 61

Propargyl ++++ 63

Propargyl ++++ + K_(i) < 10,000 nM; ++ K_(i) < 1,000 nM; +++ K_(i) < 500nM; ++++ K_(i) < 100 nM.Synthesis:

(S)-1,1-Ethynyl-hydroxy-(R)-3-methylcyclohexane. A solution of 0.5 Methynylmagnesium bromide in THF (150.0 mL, 0.0750 mol) was added to anice cold solution of (R)-(+)-3-methylcyclohexanone (2.77 g, 0.02469 mol)in anhydrous THF (100 mL). The ice bath was removed and the mixturestirred at room temperature 24 h. The mixture was cooled over ice andquenched with water (15.0 mL). The volume of THF was reduced toapproximately 50 mL and the mixture filtered through a bed ofcelite/sand, washing with ether. The solution is then evaporated todryness and the crude purified by column chromatography, eluting with agradient of hexanes to hexanes/ethyl acetate (10%) to afford the pureproduct as a white crystalline solid: yield 1.412 g, 41%. ¹H NMR (CDCl₃)δ 0.73–0.95, 1.10–1.19, 1.35–1.45, 1.51–1.84, 1.93–2.03 (5×m, 9H,cyclohexyl), 0.93 (d, 3H, —CH₃), 2.48 (s, 1H, alkyne).

2-Ethynyl-adamantan-2-ol. A solution of 0.5 M ethynylmagnesium bromidein THF (400.0 mL, 0.2000 mol) was added to an ice cold solution of2-adamantone (7.706 g, 0.05130 mol) in anhydrous THF (250 mL). Themixture was stirred over ice 0.5 h and then at room temperature 21 h.The volume was reduced to half and the solution cooled over ice. Thereaction was quenched with water (5.0 mL), filtered through a bed ofcelite/sand and evaporated to dryness. The crude was taken up in ether(400 mL) and washed with water (2×40 mL) and brine (50 mL), dried overMgSO₄, filtered, and evaporated to dryness to afford the pure product asa crystalline white solid: yield 8.961 g, 99%. ¹H NMR (CDCl₃) δ1.54–1.61, 1.68–1.72, 1.76–1.99, 2.11–2.21 (4×m, 14H, adamantly), 2.53(s, 1H, alkyne).

Representative procedure for N6-amino substitution: 2-Iodoadenosine. Asuspension of6-chloro-2-iodo-9-(2′,3′,5′-O-triacetylfuranosyl)-9H-purine (14.70 g,0.02729 mol) in MeOH (300 mL) was cooled over an ice bath. Ammonia gaswas then bubbled through the mixture until it was saturated. Thereaction vessel was sealed and heated at 40° C. for 18 h and at 60° C.for 5 days. The mixture was cooled over ice and nitrogen gas bubbledthrough the solution, the mixture being allowed to warm to roomtemperature. The solvent was then removed under reduced pressure and thecrude recrystallized from water containing 3–4 drops of glacial aceticacid. The resulting precipitate was filtered and washed with water andether to afford a white solid: yield 7.167 g, 67%.

Representative procedure for N6-alkylamino substitution:2-Iodo-6-(3-pentyl)adenosine.6-chloro-2-iodo-9-(2′,3′,5′-O-triacetylfuranosyl)-9H-purine (6.723 g,0.01248 mol), 3-aminopentane (1.673 mL, 0.01436 mol) anddiisopropylethylamine (2.725 mL, 0.01560 mol) were stirred in denaturedethanol (150 mL) at 90° C. in a pressure apparatus for 21 h. Thereaction was then cooled over ice and ammonia gas bubbled through themixture until it was saturated. The reaction vessel was closed and themixture stirred at room temperature 21 h. The mixture was cooled overice and nitrogen gas bubbled through the solution, the mixture beingallowed to warm to room temperature. The solvent was removed underreduced pressure and the crude purified by column chromatography,eluting with a gradient of DCM/MeOH (0–4%) to afford the pure product asan off white solid: yield 4.838 g, 84%.

Representative procedure for C2 coupling:2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine. To a solution of2-iodoadenosine (3.105 g, 7.898 mmol) in freshly degassedacetonitrile/DMF (100 mL, 1:1) was added degassed triethylamine (11.0mL, 78.9 mmol), Pd(PPh₃)₄ (113 mg, 0.09779 mmol), CuI (catalytic), and2,2-ethynyl-hydroxy-adamantanyl (1.516 g, 8.601 mmol). The mixture wasstirred at room temperature under and inert atmosphere for 71 h. Silicabound Pd(II) scavenger Si-thiol (561 mg) and Pd(0) scavenger Si-TAAcOH(541 mg) were added and stirring continued a further 4.5 h. Thesuspension was filtered through celite and the resulting solutionevaporated to dryness. The crude was purified by column chromatography,eluting with a gradient of DCM/MeOH (0–15%) to afford the pure productas a white solid: yield 3.476 g, 100%.

Representative procedure for ribose cleavage:2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine. A solution of2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenosine (3.486 g, 7.896 mmol)in methanol (100 mL) and 1.0 M HCl (10.0 mL) was stirred at 90° C. in apressure apparatus for 18–50 h. The pH was adjusted to 4.2 with 5.0 MNaOH and the volume was reduced to half under reduced pressure. Aftercooling the resulting precipitate was filtered and washed with methanolto afford the pure product as a white solid: yield 2.153 g, 88%. ¹H NMR(DMSO-d₆) δ 8.13 (s, 1H), 7.25 (br s, 2H), 5.56 (s, 1H), 2.18–2.09,1.94–1.89, 1.82–1.64, 1.52–1.45 (4×m, 12H). LRMS ESI (M+H⁺) 310.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine.Using the representative procedure for ribose cleavage above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenosine(1.03 g) gave the product as a white solid: yield 0.725 g, 98%. LRMS ESI(M+H⁺) 342.2.

Synthesis of C2, N9-Adenines:

Representative Procedure for N9-alklation using an Appropriate AlkylHalide:

An appropriate 9-unsubstituted adenine (1.649 mmol) was dissolved in DMF(80 mL). Anhydrous potassium carbonate (358 mg, 2.590 mmol) and anappropriate alkyl halide (3.295 mmol) were added and the mix stirred atbetween 25–100° C. for 5–100 h. The reaction mixture was adhered tosilica and purified by column chromatography, eluting with a gradient ofDCM/MeOH (0–10%) to afford the pure product.

9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(1). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (29 mg)gave 1 as a white solid: yield 19 mg, 55%. ¹H NMR (CD₃OD) δ 8.21 (s,1H), 4.06 (d, 2H, J═7.3 Hz), 2.13–2.05, 1.94–1.66, 1.49–1.28, 0.92–0.80,0.66–0.59, 0.49–0.44 (6×m, 14H), 1.17 (t, 1H, J=12.3 Hz), 0.96 (d, 2H,J=6.6 Hz). LRMS ESI (M+H⁺) 326.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine(2). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (112 mg)gave 2 as an off white solid: yield 88 mg, 69%. ¹H NMR (CD₃OD) δ 8.23(s, 1H), 5.04 (s, 2H), 2.98 (t, 1H, J=2.6 Hz), 2.13–2.05, 1.94–1.65,1.49–1.38, 0.91–0.80, (4×m, 7H), 1.17 (t, 1H, J=12.3 Hz), 0.95 (d, 2H,J=6.6 Hz). LRMS ESI (M+H⁺) 310.1.

9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(3). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (34 mg)gave 3 as a white solid: yield 21 mg, 50%. ¹H NMR (CD₃OD) δ 8.21 (s,1H), 4.91 (tt, 1H, J=7.0 Hz), 2.31–2.19, 2.13–1.65, 1.49–1.38, 0.92–0.79(4×m, 17H), 1.15 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI(M+H⁺) 340.2.

9-Acetonitrile-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(4). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (43 mg)gave 4 as a white solid: yield 25 mg, 51%. ¹H NMR (CD₃OD) δ 8.20 (s,1H), 5.35 (s, 1H),2.33–2.05, 1.93–1.66, 1.49–1.38, 0.92–0.80 (4×m, 9H),1.18 (t, 1H, J=12.3 Hz), 0.96 (d, 2H, J=6.6 Hz). LRMS ESI (M+H⁺) 311.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-methoxybenzyl)adenine(5). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (24 mg)gave 5 as a white solid: yield 29 mg, 84%. ¹H NMR (CD₃OD) δ 8.10 (s,1H), 7.26 (d, 2H, J=8.8 Hz), 6.88 (d, 2H, J=8.8 Hz), 5.32 (s, 2H), 3.75(s, 3H), 2.33–2.05, 1.92–1.66, 1.49–1.38, 0.92–0.80 (4×m, 9H), 1.17 (t,1H, J=12.3 Hz), 0.95 (d, 2H, J=6.6 Hz). LRMS ESI (M+H⁺) 392.2.

9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(6). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26 mg)gave 6 as a white solid: yield 28 mg, 68%. ¹H NMR (CD₃OD) δ 8.20 (s,1H), 7.52 (d, 1H, J=2.1 Hz), 7.48 (d, 1H, J=8.3 Hz), 7.19 (dd, 1H, J=2.1Hz, J=8.3 Hz), 5.40 (s, 2H), 2.11–2.04, 1.92–1.64, 1.48–1.37, 0.92–0.79(4×m, 9H), 1.16 (t, 1H, J=12.3 Hz), 0.94 (d, 2H, J=6.6 Hz). LRMS ESI(M+H⁺) 430.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-trifluoromethylbenzyl)adenine(7). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (30 mg)gave 7 as a white solid: yield 33 mg, 70%. ¹H NMR (CD₃OD) δ 8.20 (s,1H), 7.64 (d, 2H, J=8.2 Hz), 7.44 (d, 2H, J=8.1 Hz), 5.52 (s, 2H),2.10–2.03, 1.90–1.63, 1.47–1.36, 0.90–0.78 (4×m, 9H), 1.15 (t, 1H,J=12.3 Hz), 0.93 (d, 2H, J=6.6 Hz). LRMS ESI (M+H⁺) 430.1.

9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(8). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (32 mg)gave 8 as a white solid: yield 36 mg, 80%. ¹H NMR (CD₃OD) δ 8.15 (s,1H), 5.20 (s, 2H), 2.50 (s, 3H), 2.22 (s, 3H), 2.11–2.03, 1.92–1.65,1.49–1.38, 0.92–0.81 (4×m, 9H), 1.18 (t, 1H, J=12.2 Hz), 0.96 (d, 2H,J=6.6 Hz). LRMS ESI (M+H⁺) 381.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifluoromethylphenyl)thiazol-4-ylmethyl]adenine(9). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine (26 mg)gave 9 as a white solid: yield 30 mg, 61%. ¹H NMR (CD₃OD) δ 8.31 (s,1H), 8.09 (d, 2H, J=8.8 Hz), 7.74 (d, 2H, J=8.3 Hz), 7.55 (s, 1H), 5.58(s, 2H), 2.12–2.04 1.91–1.64, 1.48–1.37, 0.91–0.78 (4×m, 9H), 1.16 (t,1H, J=12.4 Hz), 0.94 (d, 2H, J=6.6 Hz). LRMS ESI (M+H⁺) 513.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-ynyl)adenine(10). To a solution of2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine(30 mg, 0.09697 mmol) in freshly degassed acetonitrile/DMF (15 mL, 2:1)was added degassed triethylamine (1.0 mL, 7.0175 mmol), Pd(PPh₃)₄ (30mg, 0.02596 mmol), CuI (catalytic), and 98+% 2-bromothiophene (13.7 μL,0.1161 mmol). The mixture was stirred at room temperature under andinert atmosphere for 28 h. Silica bound Pd(II) scavenger Si-thiol (240mg) and Pd(0) scavenger Si-TAAcOH (155 mg) were added and stirringcontinued a further 72 h. The suspension was filtered through celite andthe resulting solution evaporated to dryness. The crude was purified bycolumn chromatography, eluting with a gradient of DCM/MeOH (0–6%) toafford the impure product (27 mg). The product was further purified byreverse phase column chromatography, eluting with a gradient of H₂/MeOH(50–75%) to afford the pure product 10 as a white solid: yield 8.5 mg,22%. ¹H NMR (CD₃OD) δ 8.27 (s, 1H), 7.41(dd, 1H, J=1.1 Hz, J=5.3 Hz),7.25 (dd, 2H, J=1.1 Hz, J=3.5 Hz), 6.99 (dd, 1H, J=3.7 Hz, J=5.0 Hz),5.29 (s, 2H), 2.14–2.05, 1.94–1.65, 1.49–1.37, 0.99–0.79 (4×m, 12H),1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 392.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-methyl-N6-(3-pentyl)adenine(11). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(20 mg) gave 11 as a white solid: yield 9 mg, 43%. ¹H NMR (CD₃OD) δ 8.02(s, 1H), 4.23 (m, 1H), 3.79 (s, 3H), 2.14–2.06, 1.96–1.38, 0.99–0.80(3×m, 20H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H⁺⁾ 356.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-propyladenine(12). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(29 mg) gave 12 as a white solid: yield 26 mg, 80%. ¹H NMR (CD₃OD) δ8.08 (s, 1H), 4.28–4.13 (m, 3H), 2.15–2.06, 1.95–1.38, 0.99–0.80 (3×m,26H), 1.17 (t, 1H, J=12.3 Hz). LRMS ESI (M+H⁺) 384.3.

9-Isobutyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(13). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(27 mg) gave 13 as a white solid: yield 23 mg, 73%. ¹H NMR (CD₃OD) δ8.06 (s, 1H), 4.21 (m, 1H), 4.01 (d, 2H, J=7.4 Hz), 2.21 (septet, 1H,J=6.8 Hz), 2.12–2.05, 1.96–1.38, 0.98–0.81 (3×m, 27H), 1.17 (t, 1H,J=12.2 Hz). LRMS ESI (M+H⁺) 398.2.

9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(14). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(30 mg) gave 14 as a white solid: yield 17 mg, 57%. ¹H NMR (CD₃OD) δ8.15 (s, 1H), 4.22 (m, 1H), 4.05 (d, 2H, J=7.3 Hz), 2.14–2.05,1.96–1.28, 0.98–0.79 (3×m, 22H), 1.17 (t, 1H, J=12.2 Hz), 0.65–0.58 (m,2H), 0.48–0.44 (m, 2H). LRMS ESI (M+H⁺) 396.3.

9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(15). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(37 mg) gave 15 as a white solid: yield 29 mg, 65%. ¹H NMR (CD₃OD) δ8.15 (s, 1H), 4.91 (tt, 1H, J=7.0 Hz), 4.21 (m, 1H), 2.31–2.17,2.14–1.35, 0.98–0.79 (3×m, 29H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI(M+H⁺) 410.3.

9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(16). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(33 mg) gave 16 as a white solid: yield 26 mg, 71%. ¹H NMR (CDCl₃) δ7.77 (br s, 1H), 6.09–5.95 (m, 1H), 5.34–5.20 (m, 2H), 4.79 (dt, 2H,J=5.8 Hz, J=1.5 Hz), 4.28 (m, 1H), 2.21–2.11, 1.96–1.42, 0.96–0.78 (3×m,21H), 1.23 (t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 382.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(propargyl)adenine(17). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(134 mg) gave 17 as a white solid: yield 79 mg, 53%. ¹H NMR (CD₃OD) δ8.17 (s, 1H), 5.03 (d, 2H, J=2.6 Hz), 4.22 (m, 1H), 2.97 (t, 1H, J=2.6),2.14–2.06, 1.95–1.38, 0.98–0.80 (3×m, 21H), 1.17 (t, 1H, J=12.4 Hz).LRMS ESI (M+H⁺) 380.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pent-4-yne)adenine(18). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(35 mg) gave 18 as a white solid: yield 31 mg, 74%. ¹H NMR (CD₃OD) δ8.07 (s, 1H), 4.32 (t, 2H, J=6.9 Hz), 4.21 (m, 1H), 2.31–2.19,2.14–2.00, 1.95–1.38, 1.00–0.79 (4×m, 21H), 1.17 (t, 1H, J=12.3 Hz).LRMS ESI (M+H⁺) 408.1.

9-(2-Hydroxyethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(19). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(103 mg) gave 19 as a white solid: yield 60 mg, 52%. ¹H NMR (CD₃OD) δ8.06 (s, 1H), 4.30 (t, 2H, J=5.1 Hz), 4.22 (m, 1H), 3.86 (t, 2H, J=5.1Hz), 2.14–2.05, 1.95–1.38, 0.99–0.80 (3×m, 21H), 1.17 (t, 1H, J=12.2Hz). LRMS ESI (M+H⁺) 386.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(3-hydroxypropyl)-N6-(3-pentyl)adenine(20). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(59 mg) gave 20 as a white solid: yield 35 mg, 51%. ¹H NMR (CD₃OD) δ8.11 (s, 1H), 4.32 (t, 2H, J=7.0 Hz), 4.20 (m, 1H), 3.56 (t, 2H, J=5.9Hz), 2.14–2.00, 1.93–1.38, 0.99–0.80 (3×m, 23H), 1.17 (t, 1H, J=12.2Hz). LRMS ESI (M+H⁺) 400.3.

9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(21). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(38 mg) gave 21 as a white solid: yield 28 mg, 62%. ¹H NMR (CD₃OD) δ8.11 (s, 1H), 4.55 (t, 2H, J=5.7 Hz), 4.22 (m, 1H), 3.96 (t, 2H, J=5.7Hz), 2.14–2.05, 1.94–1.38, 0.99–0.79 (3×m, 21H), 1.17 (t, 1H, J=12.1Hz). LRMS ESI (M+H⁺) 404.2.

9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(22). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(37 mg) gave 22 as a white solid: yield 32 mg, 69%. ¹H NMR (CD₃OD) δ8.04 (s, 1H), 5.20 (t, 1H, J=3.3 Hz), 4.40 (d, 2H, J=3.3 Hz), 4.21 (m,1H), 3.88–3.76 (m, 4H), 2.14–2.06, 1.92–1.38, 0.98–0.79 (3×m, 21H), 1.17(t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 428.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(tetrahydro-pyran-2-ylmethyl)adenine(23). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(32 mg) gave 23 as a white solid: yield 27 mg, 66%. ¹H NMR (CD₃OD) δ8.01 (s, 1H), 4.31–4.07 (m, 3H), 3.96–3.87 (m, 1H), 3.67–3.58 (m, 1H),3.93–3.32 (m, 1H), 2.14–2.06, 1.95–1.38, 1.31–1.12, 0.99–0.80 (4×m,28H). LRMS ESI (M+H⁺) 440.4.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(isopropylcarboxylate)adenine(24). A 1.0 M solution of isopropyl chloroformate in toluene (150 μL,0.1500 mmol) was added to an ice cold solution of2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(34 mg) in anhydrous pyridine (2.0 mL). After stirring over ice 1.5 hthe solvent was removed under reduced pressure and the crude purified bycolumn chromatography, eluting with a gradient of DCM/MeOH (0–5%) toafford the pure product 24 as an off white solid: yield 18 mg, 42%. ¹HNMR (CD₃OD) δ 8.44 (s, 1H), 5.29 (septet, 1H, J=6.4, J=6.2 Hz), 4.21 (m,1H), 2.14–2.05, 1.97–1.37, 1.00–0.79 (3×m, 27H), 1.16 (t, 1H, J=12.2Hz). LRMS ESI (M+H⁺) 427.9.

9-(Acetic acid ethylester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(25). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(38 mg) gave 25 as a white solid: yield 9 mg, 19%. ¹H NMR (CD₃OD) δ 8.06(s, 1H), 5.06 (s, 2H), 4.24 (br q, 3H, J=7.0, 7.3 Hz), 2.15–2.05,1.95–1.37, 1.05–0.79 (3×m, 22H), 1.29 (t, 3H, J=7.0, 7.3 Hz), 1.17 (t,1H, J=12.2 Hz). LRMS ESI (M+H⁺) 428.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-oxazolidin-5-ylmethyl)-N6-(3-pentyl)adenine(26). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(56 mg) gave 26 as a white solid: yield 43 mg, 60%. ¹H NMR (CD₃OD) δ8.09 (s, 1H), 5.04 (m, 1H), 4.52 (d, 2H, J=4.8 Hz), 4.21 (m, 1H),3.79–3.70 (m, 1H), 3.47–3.39 (m, 1H), 2.13–2.04, 1.95–1.38, 0.99–0.79(3×m, 21H), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 441.3.

9-Benzyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(27). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(37 mg) gave 27 as a white solid: yield 31 mg, 66%. ¹H NMR (CD₃OD) δ8.06 (s, 1H), 7.37–7.25 (m, 5H), 5.40 (s, 2H), 4.22 (m, 1H), 2.14–2.05,1.95–1.37, 0.99–0.79 (3×m, 21H), 1.16 (t, 1H, J=12.3 Hz). LRMS ESI(M+H⁺) 432.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pyridin-3-ylmethyl)adenine(28). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(34 mg) gave 28 as a white solid: yield 8 mg, 19%. ¹H NMR (CD₃OD) δ 8.57(m, 1H), 8.48 (m, 1H), 8.17 (s, 1H), 7.77 (m, 1H), 7.41 (m, 1H), 5.49(s, 2H), 4.22 (m, 1H), 2.13–2.04, 1.93–1.37, 0.99–0.79 (3×m, 21H), 1.16(t, 1H, J=12.3 Hz). LRMS ESI (M+H⁺) 433.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrobenzyl)-N6-(3-pentyl)adenine(29). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(33 mg) gave 29 as a white solid: yield 36 mg, 78%. ¹H NMR (CD₃OD) δ8.19 (d, 2H, J=8.8 Hz), 8.16 (s, 1H), 7.46 (d, 2H, J=8.8 Hz), 5.55 (s,2H), 4.22 (m, 1H), 2.12–2.02, 1.92–1.36, 1.00–0.78 (3×m, 21H), 1.15 (t,1H, J=12.2 Hz). LRMS ESI (M+H⁺) 477.3.

9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(30). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(50 mg) gave 30 as a white crystalline solid: yield 50 mg, 76%. ¹H NMR(CD₃OD) δ 8.08 (s, 1H), 5.18 (s, 2H), 4.19 (m, 1H), 2.50 (s, 3H), 2.23(s, 3H), 2.13–2.04, 1.94–1.38, 0.99–0.80 (3×m, 21H), 1.18 (t, 1H, J=12.1Hz). LRMS ESI (M+H⁺) 451.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-thiazol-5-ylmethyl)-N6-(3-pentyl)adenine(31).2-{2-[1-(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(56 mg, 0.1640 mmol) and 4-chloromethyl-2-methylthiazole hydrochloride(127 mg, 0.6899 mmol) were stirred in DMF (8 mL) at 150° C. for 22 h.The reaction mixture was adhered to silica and purified by columnchromatography, eluting with a gradient of DCM/MeOH (0–6%) to affordpure 31 as an off white solid: yield 2 mg, 3%. ¹H NMR (CD₃OD) δ 8.12 (s,1H), 7.29 (s, 1H), 5.44 (s, 2H), 4.22 (m, 1H), 2.65 (s, 3H), 2.14–2.05,1.94–1.37, 0.99–0.80 (3×m, 21H), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI(M+H⁺) 453.2.

N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyl-adenine(32). Using the representative procedure for N9-alkylation aboveN6-[(S)-(+)-sec-butyl]-2-{2-[1-(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(29 mg) gave 32 as a white solid: yield 20 mg, 62%. ¹H NMR (CD₃OD) δ8.17 (s, 1H), 5.03 (d, 2H, J=2.6 Hz), 4.32 (m, 1H), 2.97 (t, 1H, J=2.6Hz), 2.14–2.06, 1.95–1.58, 1.49–1.38, 1.00–0.79 (4×m, 16H), 1.25 (d, 3H,J=6.4 Hz), 1.17 (t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 366.1.

N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(33). Using the representative procedure for N9-alkylation aboveN6-[(S)-(+)-sec-butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(42 mg) gave 33 as a white solid: yield 31 mg, 55%. ¹H NMR (CD₃OD) δ8.08 (s, 1H), 5.19 (s, 2H), 4.29 (m, 1H), 2.50 (s, 3H), 2.22 (s, 3H),2.14–2.04, 1.95–1.57, 1.49–1.38, 0.99–0.82 (4×m, 16H), 1.24 (d, 3H,J=6.4 Hz), 1.18 (t, 1H, J=12.2 Hz). LRMS ESI (M+H⁺) 437.2.

N6-(2-Diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-methyladenine(34). Using the representative procedure for N9-alkylation aboveN6-(2-diphenylethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(14 mg) gave 34 as a white solid: yield 5 mg, 35%. LRMS ESI (M+H⁺)466.3.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(s)-(−)-alpha-napthalen-1-yl-ethyl]-9-(propargyl)adenine(35). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-1(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(S)-(−)-alpha-napthalen-1-yl-ethyl]adenine(29 mg) gave 35 as a white solid: yield 22 mg, 70%. ¹H NMR (CD₃OD) δ8.23 (m, 1H), 8.15 (s, 1H), 7.88–7.84 (m, 1H), 7.76 (d, 1H, J=8.4 Hz),7.64 (d, 1H, J=7.0 Hz), 7.53–7.40 (m, 3H), 6.33 (br s, 1H), 5.00 (d, 2H,J=2.6 Hz), 2.96 (t, 1H, J=2.6 Hz), 2.08–1.99, 1.87–1.59, 1.45–1.33,1.18–1.08, 0.95–0.70 (3×m, 12H). LRMS ESI (M+H⁺) 464.1.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)-9-(propargyl)adenine(36). Using the representative procedure for N9-alkylation above2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)adenine(48 mg) gave 36 as a white solid: yield 40 mg, 76%. ¹H NMR (CD₃OD) δ8.14 (s, 1H), 7.18 (t, 1H, J=7.9 Hz), 6.96–6.90 (m, 2H), 6.77 (m, 1H),5.01 (d, 2H, J=2.6 Hz), 4.75 (br s, 2H), 3.74 (s, 3H), 2.97 (t, 1H,J=2.6 Hz), 2.13–2.04, 1.94–1.64, 1.48–1.37, 1.21–1.11, 0.96–0.77 (5×m,12H). LRMS ESI (M+H⁺) 430.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N6-(pyridin-2-ylmethyl)adenine(37). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(pyridin-2-ylmethyl)adenine(29 mg) gave 37 as a white solid: yield 27 mg, 84%. ¹H NMR (CD₃OD) δ8.49 (d, 1H, J=4.4 Hz), 8.20 (s, 1H), 7.76 (dt, 1H, J=1.8 Hz, J=7.7 Hz),7.43 (d, 1H, J=7.9 Hz), 7.29 (m, 1H), 5.04 (d, 2H, J=2.6 Hz), 4.91 (brs, 2H), 2.98 (t, 1H, J=2.6 Hz), 2.10–2.03, 1.90–1.63, 1.47–1.36,1.20–1.10, 0.96–0.73 (5×m, 12H). LRMS ESI (M+H⁺) 401.2.

2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]-9-(propargyl)adenine(38). Using the representative procedure for N9-alkylation above2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]adenine(54 mg) gave 38 as a white solid: yield 47 mg, 79%. ¹H NMR (CD₃OD) δ8.09 (s, 1H), 7.30–7.11 (m, 5H), 5.00 (d, 2H, J=2.6 Hz), 4.19 (br s,2H), 3.35 (br s, 3H), 2.98–2.91 (m, 3H), 2.14–2.06, 1.96–1.66,1.50–1.39, 1.27–1.13, 0.98–0.80 (5×m, 12H). LRMS ESI (M+H⁺) 428.3.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-methyladenine (39). Using therepresentative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (58 mg) gave 39 as awhite solid: yield 39 mg, 64%. ¹H NMR (CD₃OD) δ 8.08 (s, 1H), 3.80 (s,3H), 2.37–2.22, 2.08–2.03, 1.89–1.74, 1.64–1.57 (4×m, 14H). LRMS ESI(M+H⁺) 324.2.

9-Ethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (40). Using therepresentative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (59 mg) gave 40 as awhite solid: yield 42 mg, 65%. ¹H NMR (CD₃OD) δ 8.15 (s, 1H), 4.25 (t,2H, J=7.4 Hz), 2.36–2.22, 2.08–2.03, 1.89–1.74, 1.64–1.57 (4×m, 14H),1.47 (t, 3H, J=7.3 Hz). LRMS ESI (M+H⁺) 338.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propyladenine (41). Using therepresentative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (56 mg) gave 41 as awhite solid: yield 46 mg, 72%. ¹H NMR (CD₃OD) δ 8.13 (s, 1H), 4.17 (t,2H, J=7.2 Hz), 2.36–2.22, 2.08–2.03, 1.92–1.74, 1.64–1.57 (4×m, 16H),0.93 (t, 3H, J=7.5 Hz). LRMS ESI (M+H⁺) 352.2.

9-Hexyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (42). Using therepresentative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50 mg) gave 42 as awhite solid: yield 43 mg, 68%. ¹H NMR (CD₃OD) δ 8.13 (s, 1H), 4.21 (t,2H, J=7.0, 7.5 Hz), 2.37–2.22, 2.08–2.03, 1.91–1.74, 1.65–1.57,1.37–1.27 (5×m, 22H), 0.88 (t, 3H). LRMS ESI (M+H⁺) 394.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-nonyladenine (43). Using therepresentative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (43 mg) gave 43 as awhite solid: yield 47 mg, 78%. ¹H NMR (CD₃OD) δ 8.13 (s, 1H), 4.20 (t,2H, J=7.3 Hz), 2.36–2.22, 2.08–2.03, 1.90–1.74, 1.64–1.56, 1.35–1.23(5×m, 28H), 0.87 (t, 3H, J=7.0 Hz). LRMS ESI (M+H⁺) 436.1.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-isobutyl-adenine (44). Usingthe representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 44 as awhite solid: yield 46 mg, 75%. ¹H NMR (CD₃OD) δ 8.11 (s, 1H), 4.02 (d,2H, J=7.5 Hz), 2.36–2.16, 2.08–2.03, 1.88–1.73, 1.64–1.56, (4×m, 15H),0.91 (d, 6H, J=6.6 Hz). LRMS ESI (M+H⁺) 366.2.

9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(45). Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (33 mg) gave 45 as awhite solid: yield 11 mg, 28%. ¹H NMR (CD₃OD) δ 8.21 (s, 1H), 4.06 (d,2H, J=7.3 Hz), 2.36–2.22, 2.08–2.03, 1.89–1.74, 1.65–1.57, (4×m, 14H),1.42–1.27 (m, 1H), 0.65–0.58, 0.49–0.43 (2×m, 4H). LRMS ESI (M+H⁺)364.2.

9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (46).Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (54 mg) gave 46 as awhite crystalline solid: yield 21 mg, 32%. ¹H NMR (CD₃OD) δ 8.12 (s,1H), 4.22 (d, 2H, J=7.5 Hz), 2.87 (quintet, 1H, J=7.7 Hz), 2.37–2.22,2.09–1.74, 1.65–1.57, (3×m, 20H). LRMS ESI (M+H⁺) 378.2.

9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(47). 2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (44 mg, 0.1422mmol) was dissolved in DMF (20 mL) with heating. Anhydrous potassiumcarbonate (51 mg, 0.3690 mmol) and cyclopentylmethyl4-methylbenzenesulfonate (54 mg, 0.2123 mmol) were added and the mixturestirred at 70° C. for 72 h. Extra cyclopentylmethyl4-methylbenzenesulfonate (82 mg, 0.3224 mmol) was added and stirringcontinued at 100° C. a further 4.5 h. The reaction mixture was adheredto silica and purified by column chromatography, eluting with a gradientof DCM/MeOH (0–6%) to afford the pure 47 as a white solid: yield 38 mg,68%. 1H NMR (CD₃OD) δ 8.15 (s, 1H), 4.14 (d, 2H, J=7.7 Hz), 2.48(quintet, 1H, J=7.5 Hz), 2.37–2.22, 2.08–2.02, 1.89–1.58, 1.37–1.24(4×m, 22H). LRMS ESI (M+H⁺) 392.0.

9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (48).Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 48 as awhite solid: yield 45 mg, 70%. ¹H NMR (CD₃OD) δ 8.10 (s, 1H), 4.04 (d,2H, J=7.3Hz), 2.37–2.22, 2.09–2.03, 1.92–1.54, 1.31–0.96, (4×m, 25H).LRMS ESI (M+H⁺) 406.3.

9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49). Usingthe representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (34 mg) gave 49 as awhite solid: yield 18 mg, 45%. ¹H NMR (CD₃OD) δ 8.32 (s, 1H), 5.03 (m,1H), 2.72–2.49, 2.38–2.22, 2.04–1.74, 1.64–1.57 (4×m, 20H). LRMS ESI(M+H⁺) 364.2.

9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50).Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (473 mg) gave 50 as awhite solid: yield 371 mg, 64%. ¹H NMR (CD₃OD) δ 8.21 (s, 1H), 4.90 (m,1H), 2.37–2.20, 2.08–1.73, 1.64–1.57 (4×m, 22H). LRMS ESI (M+H⁺) 378.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine (51). Usingthe representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (510 mg) gave 51 as awhite solid: yield 416 mg, 73%. ¹H NMR (CD₃OD) δ 8.22 (s, 1H), 5.04 (d,2H, J=2.6 Hz), 2.98 (t, 1H, J=2.5 Hz), 2.36–2.22, 2.08–2.03, 1.89–1.75,1.65–1.57 (4×m, 14H). LRMS ESI (M+H⁺) 348.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxyethyl)adenine (52).Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49 mg) gave 52 as awhite solid: yield 21 mg, 38%. ¹H NMR (CD₃OD) δ 8.12 (s, 1H), 4.31 (t,2H, J=5.2 Hz), 3.87 (t, 2H, J=4.7 Hz), 2.36–2.21, 2.08–2.01, 1.89–1.73,1.65–1.57 (4×m, 14H). LRMS ESI (M+H⁺) 354.2.

2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(2-hydroxypropyl)adenine(53). Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (55 mg) gave 53 as awhite solid: yield 37 mg, 57%. ¹H NMR (CD₃OD) δ 8.13 (s, 1H), 4.32 (t,2H, J=7.0 Hz), 3.55 (t, 2H, J=5.9, 6.2 Hz), 2.36–2.21, 2.11–2.00,1.89–1.73, 1.65–1.57 (4×m, 16H). LRMS ESI (M+H⁺) 368.2.

2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine: Isomer A(60). Using the representative procedure for N9-alkylation above2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (42 mg) gave 60 as awhite solid: yield 18 mg, 38%. ¹H NMR (CD₃OD) δ 8.22 (s, 1H), 5.03 (s,2H), 2.47–2.51 (m, 1H), 2.19–2.30 (m, 2H), 1.90–2.08 (m, 2H), 1.53–1.66(m, 1H), 1.27–1.47 (m, 4H). LRMS ESI (M+H⁺) 308.1.

2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine: Isomer B(61). Using the representative procedure for N9-alkylation above2-{2-[hydroxy-norbornan-2-yl]ethyn-1-yl}adenine (31 mg) gave 61 as awhite solid: yield 10 mg, 29%. ¹H NMR (CD₃OD) δ 8.22 (s, 1H), 5.03 (s,2H), 2.47–2.51 (m, 1H), 2.19–2.30 (m, 2H), 1.90–2.08 (m, 2H), 1.53–1.66(m, 1H), 1.27–1.47 (m, 4H). LRMS ESI (M+H⁺) 308.1.

9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (62).Using the representative procedure for N9-alkylation above2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (52 mg) gave 62 as awhite solid: yield 14 mg, 24%. ¹H NMR (CD₃OD) δ 8.18 (s, 1H), 4.36 (t,2H, J=6.6 Hz), 2.77 (dt, 2H, J=2.6, 6.6 Hz), 2.36 (t, 1H, J=2.6 Hz),2.36–2.22, 2.08–2.03, 1.89–1.74, 1.64–1.57 (4×m, 16H). LRMS ESI (M+H⁺)362.0.

2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine(63). Using the representative procedure for N9-alkylation above2-{3-[1-(methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}adenine (53 mg)gave 63 as a white solid: yield 18 mg, 30%. ¹H NMR (CD₃OD) δ 8.21 (s,1H), 5.02 (s, 2H), 4.21–4.09 (m, 2H), 3.66 (s, 3H), 2.94–2.74 (m, 2H),2.47–2.40 (m, 3H), 1.95–1.74 (m, 3H), 1.38–1.20 (m, 2H). LRMS ESI (M+H⁺)353.1.

The compounds in tables 1 to 7, or their pharmaceutically acceptablesalts either as single stereoisomers or mixtures are representativeexamples of the invention.

TABLE 1

Compound (CR¹R²)_(m)-Z R⁶ NC100 Propargyl CH₂OH NC101 c-Pentyl CH₂OHNC102 Propargyl CO₂H NC103 c-Pentyl CO₂H NC104 Propargyl CO₂Me NC105c-Pentyl CO₂Me NC106 Propargyl CH₂OAc NC107 c-Pentyl CH₂OAc NC108Propargyl CH₂N(CH₃)₂ NC109 c-Pentyl CH₂N(CH₃)₂ NC110 PropargylCOOCH₂CH₂NHBoc NC111 c-Pentyl COOCH₂CH₂NHBoc NC112 PropargylCOOCH₂CH₂NH₂ NC113 c-Pentyl COOCH₂CH₂NH₂ NC114 Propargyl CONHCH₂CH₃NC115 c-Pentyl CONHCH₂CH₃ NC116 Propargyl CONH₂ NC117 c-Pentyl CONH₂NC118 Propargyl CONHMe NC119 c-Pentyl CONHMe NC120 Propargyl Me, cisCO₂Me NC121 c-Pentyl Me, cis CO₂Me NC122 Propargyl Me, trans CO₂Me NC123c-Pentyl Me, trans CO₂Me NC124 Propargyl CH₂CH₃ NC125 c-Pentyl CH₂CH₃NC126 Propargyl H NC127 c-Pentyl H NC128 Propargyl COCH₃ NC129 c-PentylCOCH₃ NC130 Propargyl CHCH₃(OH) NC131 c-Pentyl CHCH₃(OH)

TABLE 2

Compound (CR¹R²)_(m)-Z R⁶ NC132 Propargyl H NC133 c-Pentyl H NC134Propargyl CO₂tBu NC135 c-Pentyl CO₂tBu NC136 Propargyl CO₂Et NC137c-Pentyl CO₂Et NC138 Propargyl CO₂iBu NC139 c-Pentyl CO₂iBu NC140Propargyl CO₂iPr NC141 c-Pentyl CO₂iPr 63 Propargyl COMe NC142 c-PentylCOMe NC143 Propargyl COC(CH₃)₃ NC144 c-Pentyl COC(CH₃)₃ NC145 PropargylCOCH₂(CH₃)₃ NC146 c-Pentyl COCH₂(CH₃)₃ NC147 Propargyl C(O)N(CH₃)₂ NC148c-Pentyl C(O)N(CH₃)₂ NC149 Propargyl C(O)N(CH₃)Et NC150 c-PentylC(O)N(CH₃)Et NC142 Propargyl C(O)N(CH₃)iPr NC143 c-Pentyl C(O)N(CH₃)iPrNC144 Propargyl C(O)N(CH₃)iBu NC145 c-Pentyl C(O)N(CH₃)iBu NC146Propargyl C(O)NH(CH₃) NC147 c-Pentyl C(O)NH(CH₃) NC148 PropargylC(O)NH(Et) NC149 c-Pentyl C(O)NH(Et) NC150 Propargyl C(O)NH(iPr) NC142c-Pentyl C(O)NH(iPr) NC143 Propargyl C(O)NH(iBu) NC144 c-PentylC(O)NH(iBu)

TABLE 3

Compound (CR¹R²)_(m)-Z R⁶ NC151 Propargyl H NC152 c-Pentyl H NC153Propargyl 2-CH₃ NC154 c-Pentyl 2-CH₃ NC155 Propargyl 2-C(CH₃)₃ NC156c-Pentyl 2-C(CH₃)₃ NC157 Propargyl 2-C₆H₅ NC158 c-Pentyl 2-C₆H₅ 2Propargyl 3-CH₃ 3 c-Pentyl 3-CH₃ NC159 Propargyl 3-(CH₃)₂ NC160 c-Pentyl3-(CH₃)₂ NC161 Propargyl 3-CH₂CH₃ NC162 c-Pentyl 3-CH₂CH₃ NC163Propargyl 3-(CH₃)₂, 5-(CH₃)₂ NC164 c-Pentyl 3-(CH₃)₂, 5-(CH₃)₂ NC165Propargyl 4-CH₃ NC166 c-Pentyl 4-CH₃ NC167 Propargyl 4-C₂H₅ NC168c-Pentyl 4-C₂H₅ NC169 Propargyl 4-C(CH₃)₃ NC170 c-Pentyl 4-C(CH₃)₃ NC171Propargyl 4-C₆H₅ NC172 c-Pentyl 4-C₆H₅

TABLE 4

Compound (CR¹R²)_(m)-Z R⁶ NC173 Propargyl H NC174 c-Pentyl H NC175Propargyl cyclohexyl NC176 c-Pentyl cyclohexyl NC177 Propargyl CO₂EtNC178 c-Pentyl CO₂Et NC179 Propargyl CO₂tBu NC180 c-Pentyl CO₂tBu NC181Propargyl COMe NC182 c-Pentyl COMe NC183 Propargyl CO₂iBu NC184 c-PentylCO₂iBu NC185 Propargyl 2-Pyrimidinyl NC186 c-Pentyl 2-Pyrimidinyl NC187Propargyl COC(CH₃)₃ NC188 c-Pentyl COC(CH₃)₃ NC189 Propargyl COMe NC190c-Pentyl COMe NC191 Propargyl COCH₂(CH₃)₃ NC192 c-Pentyl COCH₂(CH₃)₃NC193 Propargyl COCH₃ NC194 c-Pentyl COCH₃ NC195 Propargyl C(O)N(CH₃)₂NC196 c-Pentyl C(O)N(CH₃)₂ NC197 Propargyl C(O)N(CH₃)Et NC198 c-PentylC(O)N(CH₃)Et NC199 Propargyl C(O)N(CH₃)iPr NC200 c-Pentyl C(O)N(CH₃)iPrNC201 Propargyl C(O)N(CH₃)iBu NC202 c-Pentyl C(O)N(CH₃)iBu NC203Propargyl C(O)NH(CH₃) NC204 c-Pentyl C(O)NH(CH₃) NC205 PropargylC(O)NH(Et) NC206 c-Pentyl C(O)NH(Et) NC207 Propargyl C(O)NH(iPr) NC208c-Pentyl C(O)NH(iPr) NC209 Propargyl C(O)NH(iBu) NC210 c-PentylC(O)NH(iBu) NC211 Propargyl CH₂OH NC212 c-Pentyl CH₂OH NC213 PropargylCO₂H NC214 c-Pentyl CO₂H NC215 Propargyl CO₂Me NC216 c-Pentyl CO₂MeNC217 Propargyl CO₂Et NC218 c-Pentyl CO₂Et NC219 Propargyl CH₂OAc NC220c-Pentyl CH₂OAc NC221 Propargyl CH₂N(CH₃)₂ NC222 c-Pentyl CH₂N(CH₃)₂NC223 Propargyl COOCH₂CH₂NHBoc NC224 c-Pentyl COOCH₂CH₂NHBoc NC225Propargyl COOCH₂CH₂NH₂ NC226 c-Pentyl COOCH₂CH₂NH₂ NC227 PropargylCONHCH₂CH₃ NC228 c-Pentyl CONHCH₂CH₃ NC229 Propargyl CONH₂ NC230c-Pentyl CONH₂ NC231 Propargyl CONHMe NC232 c-Pentyl CONHMe NC233Propargyl CH₂CH₃ NC234 c-Pentyl CH₂CH₃ NC235 Propargyl COCH₃ NC236c-Pentyl COCH₃ NC237 Propargyl CHCH₃(OH) NC238 c-Pentyl CHCH₃(OH)

TABLE 5

Compound (CR¹R²)_(m)-Z R⁶ NC211 Propargyl CH₂OH NC212 c-Pentyl CH₂OHNC213 Propargyl CO₂H NC214 c-Pentyl CO₂H NC215 Propargyl CO₂Me NC216c-Pentyl CO₂Me NC217 Propargyl CO₂Et NC218 c-Pentyl CO₂Et NC219Propargyl CH₂OAc NC220 c-Pentyl CH₂OAc NC221 Propargyl CH₂N(CH₃)₂ NC222c-Pentyl CH₂N(CH₃)₂ NC223 Propargyl COOCH₂CH₂NHBoc NC224 c-PentylCOOCH₂CH₂NHBoc NC225 Propargyl COOCH₂CH₂NH₂ NC226 c-Pentyl COOCH₂CH₂NH₂NC227 Propargyl CONHCH₂CH₃ NC228 c-Pentyl CONHCH₂CH₃ NC229 PropargylCONH₂ NC230 c-Pentyl CONH₂ NC231 Propargyl CONHMe NC232 c-Pentyl CONHMeNC233 Propargyl CH₂CH₃ NC234 c-Pentyl CH₂CH₃ NC235 Propargyl COCH₃ NC236c-Pentyl COCH₃ NC237 Propargyl CHCH₃(OH) NC238 c-Pentyl CHCH₃(OH)

TABLE 6

Compound (CR¹R²)_(m)-Z R⁶ NC239 Propargyl CH₂OH NC240 c-Pentyl CH₂OHNC241 Propargyl CO₂H NC242 c-Pentyl CO₂H NC243 Propargyl CO₂Me NC244c-Pentyl CO₂Me NC245 Propargyl CH₂OAc NC246 c-Pentyl CH₂OAc NC247Propargyl CH₂N(CH₃)₂ NC248 c-Pentyl CH₂N(CH₃)₂ NC249 PropargylCOOCH₂CH₂NHBoc NC250 c-Pentyl COOCH₂CH₂NHBoc NC251 PropargylCOOCH₂CH₂NH₂ NC252 c-Pentyl COOCH₂CH₂NH₂ NC253 Propargyl CONHCH₂CH₃NC254 c-Pentyl CONHCH₂CH₃ NC255 Propargyl CONH₂ NC256 c-Pentyl CONH₂NC257 Propargyl CONHMe NC258 c-Pentyl CONHMe NC259 Propargyl CH₂CH₃NC260 c-Pentyl CH₂CH₃ NC261 Propargyl COCH₃ NC262 c-Pentyl COCH₃ NC263Propargyl CHCH₃(OH) NC264 c-Pentyl CHCH₃(OH)

TABLE 7

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z W W′ R⁶ NC265 Propargyl CH CH CO₂MeNC266 c-Pentyl CH N CO₂Me NC267 Propargyl N CH CO₂Me NC268 c-Pentyl N NCO₂Me NC269 Propargyl CH CH CO₂Me NC270 c-Pentyl CH N CO₂Me NC271Propargyl N CH CO₂Me NC272 c-Pentyl N N CO₂Me NC273 Propargyl CH CHCH₂OH NC274 c-Pentyl CH N CH₂OH NC275 Propargyl N CH CH₂OH NC276c-Pentyl N N CH₂OH NC277 Propargyl CH CH CH₂OH NC278 c-Pentyl CH N CH₂OHNC279 Propargyl N CH CH₂OH NC280 c-Pentyl N N CH₂OH NC281 Propargyl CHCH CO₂H NC282 c-Pentyl CH N CO₂H NC283 Propargyl N CH CO₂H NC284c-Pentyl N N CO₂H NC285 Propargyl CH CH CO₂H NC286 c-Pentyl CH N CO₂HNC287 Propargyl N CH CO₂H NC288 c-Pentyl N N CO₂H NC289 Propargyl CH CHCH₂OAc NC290 c-Pentyl CH N CH₂OAc NC291 Propargyl N CH CH₂OAc NC292c-Pentyl N N CH₂OAc NC293 Propargyl CH CH CH₂OAc NC294 c-Pentyl CH NCH₂OAc NC295 Propargyl N CH CH₂OAc NC296 c-Pentyl N N CH₂OAc NC297Propargyl CH CH CONH₂ NC298 c-Pentyl CH N CONH₂ NC299 Propargyl N CHCONH₂ NC300 c-Pentyl N N CONH₂ NC301 Propargyl CH CH CONH₂ NC302c-Pentyl CH N CONH₂ NC303 Propargyl N CH CONH₂ NC304 c-Pentyl N N CONH₂NC305 Propargyl CH CH CONHMe NC306 c-Pentyl CH N CONHMe NC307 PropargylN CH CONHMe NC308 c-Pentyl N N CONHMe NC309 Propargyl CH CH CONHMe NC310c-Pentyl CH N CONHMe NC311 Propargyl N CH CONHMe NC312 c-Pentyl N NCONHMe NC313 Propargyl CH CH CO₂tBu NC314 c-Pentyl CH N CO₂tBu NC315Propargyl N CH CO₂tBu NC316 c-Pentyl N N CO₂tBu NC317 Propargyl CH CHCO₂tBu NC318 c-Pentyl CH N CO₂tBu NC319 Propargyl N CH CO₂tBu NC320c-Pentyl N N CO₂tBu NC321 Propargyl CH CH CO₂Et NC322 c-Pentyl CH NCO₂Et NC323 Propargyl N CH CO₂Et NC324 c-Pentyl N N CO₂Et NC325Propargyl CH CH CO₂Et NC326 c-Pentyl CH N CO₂Et NC327 Propargyl N CHCO₂Et NC328 c-Pentyl N N CO₂Et NC329 Propargyl CH CH CO₂iBu NC330c-Pentyl CH N CO₂iBu NC331 Propargyl N CH CO₂iBu NC332 c-Pentyl N NCO₂iBu NC333 Propargyl CH CH CO₂iBu NC334 c-Pentyl CH N CO₂iBu NC335Propargyl N CH CO₂iBu NC336 c-Pentyl N N CO₂iBu NC337 Propargyl CH CHCO₂iPr NC338 c-Pentyl CH N CO₂iPr NC339 Propargyl N CH CO₂iPr NC340c-Pentyl N N CO₂iPr NC341 Propargyl CH CH CO₂iPr NC342 c-Pentyl CH NCO₂iPr NC343 Propargyl N CH CO₂iPr NC344 c-Pentyl N N CO₂iPr NC345Propargyl CH CH COMe NC346 c-Pentyl CH N COMe NC347 Propargyl N CH COMeNC348 c-Pentyl N N COMe NC349 Propargyl CH CH COMe NC350 c-Pentyl CH NCOMe NC351 Propargyl N CH COMe NC352 c-Pentyl N N COMe NC353 PropargylCH CH COC(CH₃)₃ NC354 c-Pentyl CH N COC(CH₃)₃ NC355 Propargyl N CHCOC(CH₃)₃ NC356 c-Pentyl N N COC(CH₃)₃ NC357 Propargyl CH CH COC(CH₃)₃NC358 c-Pentyl CH N COC(CH₃)₃ NC359 Propargyl N CH COC(CH₃)₃ NC360c-Pentyl N N COC(CH₃)₃ NC361 Propargyl CH CH COCH₂(CH₃)₃ NC362 c-PentylCH N COCH₂(CH₃)₃ NC363 Propargyl N CH COCH₂(CH₃)₃ NC364 c-Pentyl N NCOCH₂(CH₃)₃ NC365 Propargyl CH CH COCH₂(CH₃)₃ NC366 c-Pentyl CH NCOCH₂(CH₃)₃ NC367 Propargyl N CH COCH₂(CH₃)₃ NC368 c-Pentyl N NCOCH₂(CH₃)₃ NC369 Propargyl CH CH C(O)N(CH₃)₂ NC370 c-Pentyl CH NC(O)N(CH₃)₂ NC371 Propargyl N CH C(O)N(CH₃)₂ NC372 c-Pentyl N NC(O)N(CH₃)₂ NC373 Propargyl CH CH C(O)N(CH₃)₂ NC374 c-Pentyl CH NC(O)N(CH₃)₂ NC375 Propargyl N CH C(O)N(CH₃)₂ NC376 c-Pentyl N NC(O)N(CH₃)₂ NC377 Propargyl CH CH C(O)N(CH₃)Et NC378 c-Pentyl CH NC(O)N(CH₃)Et NC379 Propargyl N CH C(O)N(CH₃)Et NC380 c-Pentyl N NC(O)N(CH₃)Et NC381 Propargyl CH CH C(O)N(CH₃)Et NC382 c-Pentyl CH NC(O)N(CH₃)Et NC383 Propargyl N CH C(O)N(CH₃)Et NC384 c-Pentyl N NC(O)N(CH₃)Et NC385 Propargyl CH CH C(O)N(CH₃)iPr NC386 c-Pentyl CH NC(O)N(CH₃)iPr NC387 Propargyl N CH C(O)N(CH₃)iPr NC388 c-Pentyl N NC(O)N(CH₃)iPr NC389 Propargyl CH CH C(O)N(CH₃)iPr NC390 c-Pentyl CH NC(O)N(CH₃)iPr NC391 Propargyl N CH C(O)N(CH₃)iPr NC392 c-Pentyl N NC(O)N(CH₃)iPr NC393 Propargyl CH CH C(O)N(CH₃)iBu NC394 c-Pentyl CH NC(O)N(CH₃)iBu NC395 Propargyl N CH C(O)N(CH₃)iBu NC396 c-Pentyl N NC(O)N(CH₃)iBu NC397 Propargyl CH CH C(O)N(CH₃)iBu NC398 c-Pentyl CH NC(O)N(CH₃)iBu NC399 Propargyl N CH C(O)N(CH₃)iBu NC400 c-Pentyl N NC(O)N(CH₃)iBu NC401 Propargyl CH CH C(O)NH(Et) NC402 c-Pentyl CH NC(O)NH(Et) NC403 Propargyl N CH C(O)NH(Et) NC404 c-Pentyl N N C(O)NH(Et)NC405 Propargyl CH CH C(O)NH(Et) NC406 c-Pentyl CH N C(O)NH(Et) NC407Propargyl N CH C(O)NH(Et) NC408 c-Pentyl N N C(O)NH(Et) NC409 PropargylCH CH C(O)NH(iPr) NC410 c-Pentyl CH N C(O)NH(iPr) NC411 Propargyl N CHC(O)NH(iPr) NC412 c-Pentyl N N C(O)NH(iPr) NC413 Propargyl CH CHC(O)NH(iPr) NC414 c-Pentyl CH N C(O)NH(iPr) NC415 Propargyl N CHC(O)NH(iPr) NC416 c-Pentyl N N C(O)NH(iPr) NC417 Propargyl CH CHC(O)NH(iBu) NC418 c-Pentyl CH N C(O)NH(iBu) NC419 Propargyl N CHC(O)NH(iBu) NC420 c-Pentyl N N C(O)NH(iBu) NC421 Propargyl CH CHC(O)NH(iBu) NC422 c-Pentyl CH N C(O)NH(iBu) NC423 Propargyl N CHC(O)NH(iBu) NC424 c-Pentyl N N C(O)NH(iBu) NC425 Propargyl CH CHCH₂OCOCH₃ NC426 c-Pentyl CH N CH₂OCOCH₃ NC427 Propargyl N CH CH₂OCOCH₃NC428 c-Pentyl N N CH₂OCOCH₃ NC429 Propargyl CH CH CH₂OCOCH₃ NC430c-Pentyl CH N CH₂OCOCH₃ NC431 Propargyl N CH CH₂OCOCH₃ NC432 c-Pentyl NN CH₂OCOCH₃ NC433 Propargyl CH CH CH₂OCOEt NC434 c-Pentyl CH N CH₂OCOEtNC435 Propargyl N CH CH₂OCOEt NC436 c-Pentyl N N CH₂OCOEt NC437Propargyl CH CH CH₂OCOEt NC438 c-Pentyl CH N CH₂OCOEt NC439 Propargyl NCH CH₂OCOEt NC440 c-Pentyl N N CH₂OCOEt NC441 Propargyl CH CH CH₂OCOiPrNC442 c-Pentyl CH N CH₂OCOiPr NC443 Propargyl N CH CH₂OCOiPr NC444c-Pentyl N N CH₂OCOiPr NC445 Propargyl CH CH CH₂OCOiPr NC446 c-Pentyl CHN CH₂OCOiPr NC447 Propargyl N CH CH₂OCOiPr NC448 c-Pentyl N N CH₂OCOiPrNC449 Propargyl CH CH CH₂OCOiBu NC450 c-Pentyl CH N CH₂OCOiBu NC451Propargyl N CH CH₂OCOiBu NC452 c-Pentyl N N CH₂OCOiBu NC453 Propargyl CHCH CH₂OCOiBu NC454 c-Pentyl CH N CH₂OCOiBu NC455 Propargyl N CHCH₂OCOiBu NC456 c-Pentyl N N CH₂OCOiBuEvaluation of Novel A_(2A) Antagonists in Four Mouse Models of PD: TheA_(2A) Receptor Antagonist ATL-2 Enhances Motor Function in aDose-dependent Manner in Normal and Dopamine-depleted Mice.

In the set of experiments, we perform a dose response study of ATL-2 instimulating motor activity in normal mice, and then we further extendthis to dopamine-depleted mice. Adult male mice are habituated for 120minutes and treated (i.p.) with saline or varying doses of compound, andtheir locomotor activity recorded for 120 minutes.

In a second set of experiments, we utilize the MPTP treatment paradigmto create animal model of PD by severely depleting dopamine in mice. Weuse a single MPTP treatment paradigm (40 mg/kg) which has beenreproducibly reducing dopamine to 30–40% of normal dopamine contents instriatum in our previous studies.^(35,74) Adult male mice (˜25 mg/kg)are treated with single dose of MPTP (40 mg/kg). Thirty minutes afterthe MPTP treatment, mice are injected (i.p.) with vehicle or compoundsof the invention at the same doses discussed above. Their motor activityis recorded for 180 minutes.

Results: Based on our previous experiments with other A_(2A)Rantagonists and our pilot study, we observe the maximal stimulant doseas well as sub-threshold doses of ATL compounds in normal andMPTP-treated mice. Without being bound by any theory, it is proposedthat motor stimulant effect may manifest best in dopamine-depletedanimals than normal animals, indicating that A_(2A)R antagonistspreferentially act at the A_(2A)R in a PD condition to stimulate motoractivity.

A_(2A) receptor antagonists synergize with L-dopa to stimulate motoractivity in dopamine-depleted mice.

We further tested the ability of these compounds to synergisticallyenhance motor function in conjunction with L-dopa, the standard therapy.Mice are injected (i.p.) with MPTP at a dose (1–2.5 mg/kg) that markedlydecreases striatal dopamine levels. Thirty minutes later (when the miceexhibit an immobility), the mice are then randomly assigned to thefollowing different treatment groups (n=10): (1) L-dopa (25 mg/kg); (2)ATL-2 (0.3, 1, 3, and 10 mg/kg), and (3) L-dopa (25 mg/kg)+ATL-2 (0.3,1, 3, and 10 mg/kg). Locomotor behavior is monitored for 120 min beforeand after the treatment.

Results: Based on the Preliminary Results and on the known feature ofother A_(2A)R antagonists, a synergistic effect of ATL-2 with L-dopa instimulating locomotor activity in dopamine-depleted mice is observed.This synergistic effect of ATL-2 and L-dopa is exhibited in a left-shiftof the dose-response curve.

A_(2A) Antagonists Potently and Specifically Attenuate MPTP-inducedNeurotoxicity by Inhibiting MPTP Metabolism.

C57Bl/6 mice (n=10–12 mice per group) are pretreated with the A_(2A)antagonist ATL-2 (0.3, 1.0, 3.0 and 10.0 mg/kg, i.p) 5 min prior to eachof four MPTP (40 mg/kg) injections at 2 hr intervals. These doses areselected based on our preliminary results (with CSC) and on motor andneuroprotective effects (against ischemia) by SCH58261 and DPCPX. Thespecificities for the A_(2A)R in these dose ranges of ATL-2 have beenconfirmed using A_(2A) KO mice. Seven days after the MPTP (±CSC,SCH58261 or CPA) treatment, the striatum from one side are dissected outand processed for HPLC analysis of dopamine and DOPAC levels. The otherhalf brain is quickly frozen for sectioning coronally through thestriatum and substantial nigra. DAT binding density in striatum may bedetermined by receptor autoradiography using ³H-mazindol as a specificligand. Quantitation of DAT (³H-mazindol) binding autoradiography may beperformed by densitometry analysis. The numbers of dopaminergic neuronsmay be determined by TH immunohistochemistry in the substantial nigra.Stereological methods may be used to estimate the absolute reduction inTH⁺ nigral neurons in MPTP-treated WT mice and any attenuation in thosepretreated with ATL-2. In the same sections, cell counts may also beperformed for TH⁺ neurons in the more medial VTA, which is less affectedin MPTP treated mice as well as in PD.

Results: Guided by our preliminary results, neuroprotection in adose-dependent manner (at least from 0.5 to 5 mg/kg range) may beobserved. The potency of A_(2A) antagonists for neuroprotection may beobserved with their potency for motor stimulation and for possibleattenuation of behavioral sensitization (see above). Similarly, thepotency of CSC or SCH58261 for neuroprotection against MPTP may becompared to that for neuroprotection against ischemic injury andexcitoxicity. A significant difference in an A_(2A) antagonist's potencyin neuroprotection against MPTP and against ischemia or excitoxicity maysuggest different mechanisms and sites of action (e.g. glial versusneuronal compartments which may have different G-protein couplingmechanisms). On the other hand, the same potency of A_(2A) antagonistsfor motor stimulation, neuroprotection and possibly delayedsensitization to L-dopa would suggest that the same type of A_(2A)R isresponsible for all these potential benefits of A_(2A) antagonists indifferent animal models of PD.

A_(2A) Antagonists Delay and A_(2A) Agonists Accelerate L-dopa-inducedLocomotor Sensitization in Unilateral 6-OHDA-lesioned Mice.

The ability of ATL-2 to modify the development of L-dopa-inducedlocomotor sensitization in hemiparkinsonian mice are tested. C57BL/6mice (from the Jackson's lab, Bar Harbor, Mich.) are lesioned with6-OHDA by unilateral intrastriatal using a standard lesioning protocol.Seven days after the 6-OHDA (or MPP⁺) treatment, mice are injected withL-dopa (2.0 mg/kg, daily) for 14 days. Five min prior to each L-dopatreatment, the mice receive intraperitoneal pretreatment with: (1)vehicle, (2) ATL-2 (3 mg/kg) or (3) ATL-2 (10 mg/kg). In these doseranges, the selective A_(2A) antagonists have been shown to producemotor stimulant effects (see Preliminary Results). Rotational responsesto L-dopa are recorded on the days 1, 3, 5, 7, 10 and 15. Following thebehavioral measurement, mice may be sacrificed and their brainssectioned through striatum and substantia nigra. Striatal enkephalinmRNA levels are determined by in situ hybridization histochemistry.Similarly, DAT (³H-mazindol) binding is measured by receptorautoradiography to ensure successful and equivalent lesions amongdifferent experimental groups.

Results: Based on our previous study with SCH58261 in this repeatedL-dopa-induced sensitization model, ATL-2 delays or prevent thedevelopment of locomotor sensitization. The prevention or delayedappearance with L-dopa locomotor sensitization by co-injection of anA_(2A) antagonist indicates an important role of the A_(2A)R in thedevelopment of L-dopa-induced behavioral sensitization. Furthermore,this helps exclude the possibility that an attenuated behavioralsensitization to chronic L-dopa observed in A_(2A) KO mice results froma developmental effect of A_(2A)R deficiency. Thus combined genetic andpharmacological approaches provide the clearest assessment of theA_(2A)R's role in the development of behavioral sensitization to L-dopa,and provides insights into its role in L-dopa-induced dyskinesia.

Methods

Animal Treatments and Catalepsy Behavioral Assessments:

WT and A_(2A) KO mice (generated as above) as well as commerciallyprocured C57Bl/6 mice (Taconic, N.Y.) may be used for this study. Sinceour pilot study and other reports [40, 88] indicate that animal age is acritical factor in determining the extent of an MPTP lesion, animal bodyweight around 25–30 grams (corresponding to approximately 10 weeks ofage) is tightly controlled. The mice are housed in temperature andhumidity-controlled rooms with a 24-hour 1:1 light:dark cycle.Adenosinergic and dopaminergic agents are injected at the volume of 0.1ml/10 gram body weight of mice. Other adenosinergic and dopaminergicdrugs are purchased from RBI (Natick, Mass.). From our previous work, wehave adapted a special solvent (15% DMSO, 15% Alkamuls-EL 620 and 70%saline) for dissolving A_(2A) antagonists, including CSC and SCH58261.

Catalepsy behavior may be induced by haloperidol (1 mg/kg, i.p.) orreserpine (5 mg/kg, i.p. see below). Catalepsy score may be determinedby the bar and grid tests. For the bar test, both mouse forepaws areplaced on a 6 cm-high horizontal bar (diameter 0.7 cm). In the gridtest, mice are allowed to cling to a metal-framed vertical grid (1.3 cmsquares). The latency from paw placement until the first completeremoval of one paw from the support is measured (maximal test duration180 sec). Upon the completion of behavioral assessment, mice aresacrificed and the brains are processed for neurochemical andhistochemical analyses.

Dopamine Depletion by the Treatment with MPTP or 6-OHDA:

a) Intraperitoneal Injection of MPTP: The MPTP administration regimen(20 mg/kg×4 at 2 hr interval) has been shown to produce severe dopaminedepletion (consistently greater than ˜80% in our Preliminary ResultsFIGS. 6 and 7). Naive C57Bl/6 mice are pretreated with adenosineantagonists 5 min prior to MPTP treatment.

b) Intrastriatal Injection of 6-OHDA: Wild-type C57Bl/6 or A2AR mutantmice are anesthetized with Avertin and positioned in a stereotaxicframe. Three microliters of 6-OHDA (3 μg/μl) are injected into the leftstriatum (coordinates from bregma: AP+0.0, L+2.5.0, DV −4.4) via ainfusion minipump over a 4 min period. Due to its photolability, 6-OHDAis dissolved in 0.01% ascorbic acid and injected under a light-protectedenvironment.

c) Post-treatment Care: Dopamine-depleted mice may be continuallymonitored, and special care may be taken to maintain mouse bodytemperature with a heating blanket or warming lights. During the first48 hours post-operation, mashed food pellets and water are provided tothe mice inside the cage at floor-level for easy access.

Neurochemical Analysis:

(a) Measurements of Catecholamines and Indoleamines in Striatum by HPLC:To measure tissue catecholamine and indoleamine levels, mice aredecapitated, their brains are removed rapidly, and striata are dissectedout and frozen on dry ice. Striata are weighed frozen and thenhomogenized in 200 μl of 150 mM trichloroacetic acid containing 0.1 mMEDTA and 1 μM epinephrine (as an internal standard). Homogenates arecentrifuged for 5 min at 15,000 g. The catecholamines in the supernatantare separated over a reverse-phase hydrophobic interaction C-18 HPLCcolumn (Beckman, 5μ ODS) and measured using an electrochemical detector(ESA Coulochem 5100A) with electrodes set in series at oxidizing (+0.22V) and then reducing (−0.35 V) potentials. Both the retention time andthe ratio of oxidation to reduction currents for given sample peaks arecompared against those for external standards to ensure properidentification of analytes.

(b) Stereologic quantitation of neuronal loss in substantia nigra: Oneweek after lesioning, mice may be perfusion-fixed and their brains maybe microtome-cut into 40 μm coronal free-floating sections. Every sixthsection may be processed for TH immunohistochemistry using a 1:1,000dilution of a polyclonal rabbit antiserum against rat TH (Eugene Tech.Intl., NJ). Immunostaining is completed using standard avidin-biotinprocedures described previously [18,130]. A non-biased stereologicaltechnique is employed to quantify the effect of treatment on total TH+nigra (pars compacta) cell counts as described previously [81]. Allcounts are performed by a single observer who is unaware of thetreatment group at the time of neuronal estimates. Based on our pilotstudies in WT mice MPP+ at this dose (3 μg/striatum) produced a ˜40%loss of ipsilateral TH+ nigral neurons.

(c) A2A receptor binding autoradiography: Twenty micron striatalsections are preincubated for 5 minutes with ice-cold buffer (509 mMTris-HCl, 5 mM KCl and 300 mM NaCl, pH 7.9) and then incubated for 60minutes in the same buffer containing 6 nM 3H-SCH58261 (providedgenerously by Dr. E. Ongini) [131]. The slides are washed twice and thenair-dried before exposure to Hyperfilm (Amersham, IL) for 2–4 weeks. Thefilms are analyzed with a video-based image analysis system(MultiAnalyst; Biorad), and total striatal 3H-SCH58261 binding (fmol/mgtissue) is calculated using a tritium-labeled calibration standard[17,131].

Statistical Analysis

Single statistical comparisons of an A2AR KO group to its WT control aregenerally performed using a Student's t test, two-tailed. Comparison ofmore than two factors (e.g. genotype, drug treatment and time course)and their interactions are made using 2-way ANOVA followed byNewman-Keuls post hoc analysis. If data are not normally distributed,non-parametric tests (Kruskal-Wallis or Mann-Whitney U test) are used.

Vertebrate Animals. Mice are the only animals that are be used inexperiments. The mice are monitored daily (co-investigators ortechnician) under the supervision of a staff veterinarian. In themajority of the experiments the mice are kept under SPF conditions withno more than 5 mice/cage of females and 4 mice/cage of males. Allhusbandry and veterinary care meets NIH and AAALAC standards for humanecare for use of laboratory animals. In addition, because of dailyobservation of all animals, any moribund animal is humanely euthanizedby CO₂.

Models of PD are used to investigate pre-clinical efficacy andpharmacokinetics of A2AAR antagonist. Because we have used these modelin our laboratory, the model is now well characterized and theexperimental manipulation of mice for these studies are wellestablished.

REFERENCES

-   1. Hauser R A, Hubble J P, Truong D D. Randomized trial of the    adenosine A(2A) receptor antagonist istradefylline in advanced PD.    Neurology. 2003;61:297–303.-   2. Lang A E, Lozano A M. Parkinson's disease. Second of two parts. N    Engl J Med. 1998; 339:1130–1143.-   3. Agid Y, Cervera P, Hirsch E, Javoy-Agid F, Lehericy S, Raisman R,    Ruberg M. Biochemistry of Parkinson's disease 28 years later: a    critical review. Mov Disord. 1989;4 Suppl 1:S126-S144.-   4. Lang A E, Lozano A M. Parkinson's disease. Second of two parts. N    Engl J Med. 1998;339:1130–1143.-   5. Lang A E, Lozano A M. Parkinson's disease. First of two parts. N    Engl J Med. 1998;339:1044–1053.-   6. Obeso J A, Olanow C W, Nutt J G. Levodopa motor complications in    Parkinson's disease. Trends Neurosci. 2000;23:S2-S7.-   7. Bezard E, Brotchie J M, Gross C E. Pathophysiology of    levodopa-induced dyskinesia: potential for new therapies. Nat Rev    Neurosci. 2001;2:577–588.-   8. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol.    2000;47:S2-S9.-   9. Fahn S. The spectrum of levodopa-induced dyskinesias. Ann Neurol.    2000;47:S2-S9.-   10. Jenner P. Pathophysiology and biochemistry of dyskinesia: clues    for the development of non-dopaminergic treatments. J Neurol.    2000;247 Suppl 2:II43-II50.-   11. Melamed E, Offen D, Shirvan A, Djaldetti R, Barzilai A, Ziv I.    Levodopa toxicity and apoptosis. Ann Neurol. 1998;44:S149-S154.-   12. Jenner P. Pathophysiology and biochemistry of dyskinesia: clues    for the development of non-dopaminergic treatments. J Neurol.    2000;247 Suppl 2:II43-II50.-   13. Chen J F. The adenosine A(2A) receptor as an attractive target    for Parkinson's disease treatment. Drug News Perspect.    2003;16:597–604.-   14. Schwarzschild M A, Chen J F, Ascherio A. Caffeinated clues and    the promise of adenosine A(2A) antagonists in PD. Neurology.    2002;58:1154–1160.-   15. Ferre S, Fredholm B B, Morelli M, Popoli P, Fuxe K.    Adenosine-dopamine receptor-receptor interactions as an integrative    mechanism in the basal ganglia. Trends Neurosci. 1997;20:482–487.-   16. Richardson P J, Gubitz A K, Freeman T C, Dixon A K. Adenosine    receptor antagonists and Parkinson's disease: actions of the A2A    receptor in the striatum. Adv Neurol. 1999;80:111–119.-   17. Schwarzschild M A, Chen J F, Ascherio A. Caffeinated clues and    the promise of adenosine A(2A) antagonists in PD. Neurology.    2002;58:1154–1160.-   18. Fink J S, Weaver D R, Rivkees S A, Peterfreund R A, Pollack A E,    Adler E M, Reppert S M. Molecular cloning of the rat A2 adenosine    receptor: selective co-expression with D2 dopamine receptors in rat    striatum. Brain Res Mol Brain Res. 1992;14:186–195.-   19. Schiffmann S N, Jacobs O, Vanderhaeghen J J. Striatal restricted    adenosine A2 receptor (RDC8) is expressed by enkephalin but not by    substance P neurons: an in situ hybridization histochemistry study.    J Neurochem. 1991;57:1062–1067.-   20. Schiffmann S N, Vanderhaeghen J J. Adenosine A2 receptors    regulate the gene expression of striatopallidal and striatonigral    neurons. J Neurosci. 1993;13:1080–1087.-   21. Ferre S, Rubio A, Fuxe K. Stimulation of adenosine A2 receptors    induces catalepsy. Neurosci Lett. 1991;130:162–164.-   22. Ferre S, Fuxe K, Von Euler G, Johansson B, Fredholm B B.    Adenosine-dopamine interactions in the brain. Neurosci.    1992;51:501–512.-   23. Fredholm B B, Battig K, Holmen J, Nehlig A, Zvartau E E. Actions    of caffeine in the brain with special reference to factors that    contribute to its widespread use. Pharmacol Rev. 1999;51:83–133.-   24. Barraco R A, Martens K A, Parizon M, Normile H J. Adenosine A2a    receptors in the nucleus accumbens mediate locomotor depression.    Brain Res Bull. 1993;31:397–404.-   25. Ferre S, Von Euler G, Johansson B, Fredholm B B, Fuxe K.    Stimulation of high-affinity adenosine A2 receptors decreases the    affinity of dopamine D2 receptors in rat striatal membranes. Proc    Natl Acad Sci USA. 1991;88:7238–7241.-   26. Fuxe K, Ferre S, Zoli M, Agnati L F. Integrated events in    central dopamine transmission as analyzed at multiple levels.    Evidence for intramembrane adenosine A2A/dopamine D2 and adenosine    A1/dopamine D1 receptor interactions in the basal ganglia. Brain Res    Brain Res Rev. 1998;26:258–273.-   27. Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in    dopamine D2 receptor-deficient mice by an adenosine A2A receptor    antagonist. J Neurosci. 2000;20:5848–5852.-   28. Chen J F, Moratalla R, Impagnatiello F, Grandy D K, Cuellar B,    Rubinstein M, Beilstein M A, Hackett E, Fink J S, Low M J, Ongini E,    Schwarzschild M A. The role of the D(2) dopamine receptor (D(2)R) in    A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular    responses as revealed by A(2A) and D(2) receptor knockout mice. Proc    Natl Acad Sci USA. 2001;98:1970–1975.-   29. Thompson R D, Secunda S, Daly J W, Olsson R A.    N6,9-disubstituted adenines: potent, selective antagonists at the A1    adenosine receptor. J Med Chem. 1991;34:2877–2882.-   30. Mori A, Shindou T, Ichimura M, Nonaka H, Kase H. The role of    adenosine A2a receptors in regulating GABAergic synaptic    transmission in striatal medium spiny neurons. J Neurosci.    1996;16:605–611.-   31. Richardson P J, Gubitz A K, Freeman T C, Dixon A K. Adenosine    receptor antagonists and Parkinson's disease: actions of the A2A    receptor in the striatum. Adv Neurol. 1999;80:111–119.-   32. Svenningsson P, Le Moine C, Fisone G, Fredholm B B.    Distribution, biochemistry and function of striatal adenosine A2A    receptors. Prog Neurobiol. 1999;59:355–396.-   33. Canals M, Marcellino D, Fanelli F, Ciruela F, de Benedetti P,    Goldberg S R, Neve K, Fuxe K, Agnati L F, Woods A S, Ferre S, Lluis    C, Bouvier M, Franco R. Adenosine A2A-dopamine D2 receptor-receptor    heteromerization: qualitative and quantitative assessment by    fluorescence and bioluminescence energy transfer. J Biol Chem.    2003;278:46741–46749.-   34. Fredholm B B, Battig K, Holmen J, Nehlig A, Zvartau E E. Actions    of caffeine in the brain with special reference to factors that    contribute to its widespread use [Review]. Pharmacol Rev.    1999;51:83–133.-   35. Chen J F, Moratalla R, Impagnatiello F, Grandy D K, Cuellar B,    Rubinstein M, Beilstein M A, Hackett E, Fink J S, Low M J, Ongini E,    Schwarzschild M A. The role of the D(2) dopamine receptor (D(2)R) in    A(2A) adenosine receptor (A(2A)R)-mediated behavioral and cellular    responses as revealed by A(2A) and D(2) receptor knockout mice. Proc    Natl Acad Sci USA. 2001;98:1970–1975.-   36. Grondin R, Bedard P J, Hadj T A, Gregoire L, Mori A, Kase H.    Antiparkinsonian effect of a new selective adenosine A2A receptor    antagonist in MPTP-treated monkeys. Neurology. 1999;52:1673–1677.-   37. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,    Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist    KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists    increases antiparkinsonian activity but not dyskinesia in    MPTP-treated monkeys. Exp Neurol. 2000;162:321–327.-   38. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,    Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel    antiparkinsonian agent that does not provoke dyskinesia in    parkinsonian monkeys. Ann Neurol. 1998;43:507–513.-   39. Kanda T, Tashiro T, Kuwana Y, Jenner P. Adenosine A2A receptors    modify motor function in MPTP-treated common marmosets. Neuroreport.    1998;9:2857–2860.-   40. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the    adenosine A(2A) receptor antagonist SCH 58261 do not develop    tolerance after repeated treatments in 6-hydroxydopamine-lesioned    rats. Synapse. 2001;39:233–238.-   41. Pinna A, di Chiara G, Wardas J, Morelli M. Blockade of A2a    adenosine receptors positively modulates turning behaviour and c-Fos    expression induced by D1 agonists in dopamine-denervated rats. Eur J    Neurosci. 1996;8:1176–1181.-   42. Aoyama S, Kase H, Borrelli E. Rescue of locomotor impairment in    dopamine D2 receptor-deficient mice by an adenosine A2A receptor    antagonist. Journal of Neuroscience. 2000;20:5848–5852.-   43. Grondin R, Bedard P J, Hadj T A, Gregoire L, Mori A, Kase H.    Antiparkinsonian effect of a new selective adenosine A2A receptor    antagonist in MPTP-treated monkeys. Neurology. 1999;52:1673–1677.-   44. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,    Kuwana Y, Jenner P. Adenosine A2A antagonist: a novel    antiparkinsonian agent that does not provoke dyskinesia in    parkinsonian monkeys. Ann Neurol. 1998;43:507–513.-   45. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,    Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist    KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists    increases antiparkinsonian activity but not dyskinesia in    MPTP-treated monkeys. Exp Neurol. 2000;162:321–327.-   46. Halldner L, Lozza G, Lindstrom K, Fredholm B B. Lack of    tolerance to motor stimulant effects of a selective adenosine A(2A)    receptor antagonist. Eur J Pharmacol. 2000;406:345–354.-   47. Pinna A, Fenu S, Morelli M. Motor stimulant effects of the    adenosine A(2A) receptor antagonist SCH 58261 do not develop    tolerance after repeated treatments in 6-hydroxydopamine-lesioned    rats. Synapse. 2001;39:233–238.-   48. Kanda T, Jackson M J, Smith L A, Pearce R K, Nakamura J, Kase H,    Kuwana Y, Jenner P. Combined use of the adenosine A(2A) antagonist    KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists    increases antiparkinsonian activity but not dyskinesia in    MPTP-treated monkeys. Exp Neurol. 2000;162:321–327.-   49. Fredduzzi S, Moratalla R, Monopoli A, Cuellar B, Xu K, Ongini E,    Impagnatiello F, Schwarzschild M A, Chen J F. Persistent behavioral    sensitization to chronic L-DOPA requires A2A adenosine receptors. J    Neurosci. 2002;22:1054–1062.-   50. Bibbiani F, Oh J D, Petzer J P, Castagnoli N, Jr., Chen J F,    Schwarzschild M A, Chase TN. A2A antagonist prevents dopamine    agonist-induced motor complications in animal models of Parkinson's    disease. Exp Neurol. 2003;184:285–294.-   51. Chen J F, Huang Z, Ma J, Zhu J, Moratalla R, Standaert D,    Moskowitz M A, Fink J S, Schwarzschild M A. A(2A) adenosine receptor    deficiency attenuates brain injury induced by transient focal    ischemia in mice. J Neurosci. 1999;19:9192–9200.-   52. Monopoli A, Casati C, Lozza G, Forlani A, Ongini E.    Cardiovascular pharmacology of the A2A adenosine receptor    antagonist, SCH 58261, in the rat. J Pharmacol Exp Ther.    1998;285:9–15.-   53. Phillis J W. The effects of selective A1 and A2a adenosine    receptor antagonists on cerebral ischemic injury in the gerbil.    Brain Res. 1995;705:79–84.-   54. Jones P A, Smith R A, Stone T W. Protection against hippocampal    kainate excitotoxicity by intracerebral administration of an    adenosine A2A receptor antagonist. Brain Res. 1998;800:328–335.-   55. Jones P A, Smith R A, Stone T W. Protection against    kainate-induced excitotoxicity by adenosine A2A receptor agonists    and antagonists. Neuroscience. 1998;85:229–237.-   56. Popoli P, Pintor A, Domenici M R, Frank C, Tebano M T, Pezzola    A, Scarchilli L, Quarta D, Reggio R, Malchiodi-Albedi F, Falchi M,    Massotti M. Blockade of striatal adenosine A2A receptor reduces,    through a presynaptic mechanism, quinolinic acid-induced    excitotoxicity: possible relevance to neuroprotective interventions    in neurodegenerative diseases of the striatum. J Neurosci.    2002;22:1967–1975.-   57. Dall'Igna O P, Porciuncula L O, Souza D O, Cunha R A, Lara D R,    Dall'Igna O P. Neuroprotection by caffeine and adenosine A2A    receptor blockade of beta-amyloid neurotoxicity. Br J Pharmacol.    2003;138:1207–1209.-   58. Chen J F, Xu K, Petzer J P, Staal R, Xu Y H, Beilstein M,    Sonsalla P K, Castagnoli K, Castagnoli N, Jr., Schwarzschild M A.    Neuroprotection by caffeine and A(2A) adenosine receptor    inactivation in a model of Parkinson's disease. J Neurosci.    2001;21:RC143.-   59. Chen J F, Xu K, Petzer J P, Staal R, Xu Y H, Beilstein M,    Sonsalla P K, Castagnoli K, Castagnoli N, Jr., Schwarzschild M A.    Neuroprotection by caffeine and A(2A) adenosine receptor    inactivation in a model of Parkinson's disease. J Neurosci.    2001;21:RC143.-   60. Ikeda K, Kurokawa M, Aoyama S, Kuwana Y. Neuroprotection by    adenosine A2A receptor blockade in experimental models of    Parkinson's disease. J Neurochem. 2002;80:262–270.-   61. Martinez-Mir M I, Probst A, Palacios J M. Adenosine A2    receptors: selective localization in the human basal ganglia and    alterations with disease. Neuroscience. 1991;42:697–706.-   62. Ross G W, Abbott R D, Petrovitch H, Morens D M, Grandinetti A,    Tung K H, Tanner C M, Masaki K H, Blanchette P L, Curb J D, Popper J    S, White L R. Association of coffee and caffeine intake with the    risk of Parkinson disease. JAMA. 2000;283:2674–2679.-   63. Ascherio A, Zhang S M, Heman M A, Kawachi I, Colditz G A,    Speizer F E, Willett W C. Prospective study of caffeine consumption    and risk of Parkinson's disease in men and women. Ann Neurol.    2001;50:56–63.-   64. Hauser R A, Hubble J P, Truong D D. Randomized trial of the    adenosine A(2A) receptor antagonist istradefylline in advanced PD.    Neurology. 2003;61:297–303.-   65. Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F,    Gillespie M, Morris M J, Mouradian M M, Chase T N. Adenosine A(2A)    receptor antagonist treatment of Parkinson's disease. Neurology.    2003;61:293–296.-   66. Bara-Jimenez W, Sherzai A, Dimitrova T, Favit A, Bibbiani F,    Gillespie M, Morris M J, Mouradian M M, Chase T N. Adenosine A(2A)    receptor antagonist treatment of Parkinson's disease. Neurology.    2003;61:293–296.-   67. Zocchi C, Ongini E, Ferrara S, Baraldi P G, Dionisotti S.    Binding of the radioligand [3H]-SCH 58261, a new non-xanthine A2A    adenosine receptor antagonist, to rat striatal membranes. Br J    Pharmacol. 1996;117:1381–1386.-   68. Keddie J R, Poucher S M, Shaw G R, Brooks R, Collis M G. In vivo    characterisation of ZM 241385, a selective adenosine A2A receptor    antagonist. Eur J Pharmacol. 1996;301:107–113.-   69. Mori A, Shindou T, Ichimura M, Nonaka H, Kase H. The role of    adenosine A2a receptors in regulating GABAergic synaptic    transmission in striatal medium spiny neurons. J Neurosci.    1996;16:605–611.-   70. Todde S, Moresco R M, Simonelli P, Baraldi P G, Cacciari B,    Spalluto G, Varani K, Monopoli A, Matarrese M, Carpinelli A, Magni    F, Kienle M G, Fazio F. Design, radiosynthesis, and biodistribution    of a new potent and selective ligand for in vivo imaging of the    adenosine A(2A) receptor system using positron emission tomography.    J Med Chem. 2000;43:4359–4362.-   71. Colotta V, Catarzi D, Varano F, Cecchi L, Filacchioni G, Martini    C, Trincavelli L, Lucacchini A.    4-Amino-6-benzylamino-1,2-dihydro-2-phenyl-1,2,4-triazolo[4,3-alpha]-quinoxalin-1-one:    a new A2A adenosine receptor antagonist with high selectivity versus    A1 receptors. Arch Pharm (Weinheim). 1999;332:39–41.-   72. Thompson R D, Secunda S, Daly J W, Olsson R A.    N6,9-disubstituted adenines: potent, selective antagonists at the A1    adenosine receptor. J Med Chem. 1991;34:2877–2882.-   73. Iwasaki K, Kusachi S, Tominaga Y, Kita T, Taniguchi G. Coronary    artery spasm demonstrated by coronary angiography in a patient with    acute myocarditis resembling acute myocardial infarction; a case    report. Jpn J Med. 1991;30:573–577.-   74. Chen J F, Steyn S, Staal R, Petzer J P, Xu K, Van Der Schyf C J,    Castagnoli K, Sonsalla P K, Castagnoli N, Jr., Schwarzschild M A.    8-(3-Chlorostyryl)caffeine may attenuate MPTP neurotoxicity through    dual actions of monoamine oxidase inhibition and A2A receptor    antagonism. J Biol Chem. 2002;277:36040–36044.

The entire disclosure of all documents cited throughout this applicationare incorporated herein by reference.

1. A compound of the formula I:

wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R¹ and R²are optionally substituted with 1 to 4 substituents of R^(a), whereinthe alkyl is optionally interrupted by 1–4 heteroatoms selected from—O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R¹ and R² areindependently absent, with the proviso that R^(a) is not SH or halogenwhen the R¹ or R² to which R^(a) is bound is halogen, —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R³ is selected from the groupconsisting of hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; or if the ring formed from the groupCR³R⁴R⁵ is aryl or heteroaryl or partially unsaturated, then R³ can beabsent; R⁴ and R⁵ together with the atoms to which they are attachedform a saturated or partially unsaturated, mono-, bi- or tricyclic oraromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms,wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, wherein any ring comprising R⁴and R⁵ is optionally further substituted with from 1 to 14 R⁶ groups;wherein each R⁶ is independently selected from the group consisting ofhalo, —OR^(a), —SR^(a), substituted or unsubstituted (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), andR^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl aryl(C₁–C₈)alkylene, heteroaryl,heteroaryl(C₁–C₈)alkylene; or wherein R⁷ and R⁸ together with thenitrogen atom to which they attach form a heterocycle or heteroaromaticring; R⁹ and R¹⁰ are each independently selected from the groupconsisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; Y is —CR³R⁴R⁵or NR⁴R⁵; Z is selected from the group consisting of halogen, vinyl,allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,1,3-bytadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl,hexa-1,3,5-trienyl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,(C₆–C₂₀)polycyclyl, heterocyclyl, cycloalkyl(C₁–C₈)alkyl,bicycloalkyl(C₆–C₁₂)alkyl, heterocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —NR^(a)R^(b),—SR^(a), cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, R^(a)OC(═S)—,R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, —OS(O₂)R^(a), —OS(═O)OR^(a),—OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b); R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen, halogen,—NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃, propargyl, cyano,—OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃, (C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl, heteroaryl andheteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkyl are optionallyinterrupted with 1–4 heteroatoms selected from the group consisting of—O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and wherein the alkyl,cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3or 4 substituents selected from the group consisting of —OR^(c),—NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃ and—OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b) isnot a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is nothalogen, cyano, or nitro or is not attached via a heteroatom, and when nis 0, Y is not —NR⁴R⁵; or a pharmaceutically acceptable salt thereof,optionally in the form of a single stereoisomer or mixture ofstereoisomers thereof.
 2. A compound of the formula II:

wherein: R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R¹ and R²are optionally substituted with 1 to 4 substituents of R^(a), whereinthe alkyl is optionally interrupted by 1 to 4 heteroatoms selected from—O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R¹ and R² areindependently absent, with the proviso that R^(a) is not thio or halogenwhen the R¹ or R² to which R^(a) is bound is halogen, —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R³ is selected from the groupconsisting of hydrogen, halo, —OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—, or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³ can be absent;R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated, mono-, bi- or tricyclic, or aromaticring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein thering atoms are optionally interrupted by 1, 2, 3 or 4 heteroatomsselected from the group consisting of —O—, —S—, —SO—, —S(O)₂— or amine(—NR^(c)—) in the ring, wherein any ring comprising R⁴ and R⁵ isoptionally further substituted with from 1 to 14 R⁶ groups; wherein eachR⁶ is independently selected from the group consisting of hydrogen,halo, —OR^(a), —SR^(a), substituted or unsubstituted (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene-; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where R⁹ and R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ and —SCH₃; L is alinker selected from the group consisting of —(C₁–C₃)alkyl-C≡C—,—C≡C—(C₁–C₃)alkyl-, —(CH₂)₁₋₃—CH═CH—, —CH═CH—(CH₂)₁₋₃—,—(CH₂)₁₋₂—CH═CH—CH₂— and —CH₂—CH═CH—(CH₂)₁₋₂—; Y is —CR³R⁴R⁵ or NR⁴R⁵; Zis selected from the group consisting of halogen, vinyl, allyl,1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,1,3-bytadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl,hexa-1,3,5-trienyl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,(C₆–C₂₀)polycyclyl, heterocyclyl, cycloalkyl(C₁–C₈)alkyl,bicycloalkyl(C₆–C₁₂)alkyl, heterocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —NR^(a)R^(b),—SR^(a), cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, R^(a)OC(═S)—,R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, —OS(O₂)R^(a), —OS(═O)OR^(a),—OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b); R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen, halogen,—NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃, propargyl, cyano,—OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃, (C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl, heteroaryl andheteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkyl are optionallyinterrupted with 1 to 4 heteroatoms selected from the group consistingof —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and wherein the alkyl,cycloalkyl, aryl and heteroaryl are optionally substituted with 1, 2, 3or 4 substituents selected from the group consisting of —OR^(c),—NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃ and—OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b) isnot a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3 provided that when m is 0, Z is nothalogen, cyano, nitro or is not attached via or a heteroatom; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 3. The compoundof claim 1, wherein (CR¹R²)_(m) together is selected from the groupconsisting of methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene, iso-propylene, iso-butylene, sec-butyleneand tert-butylene.
 4. The compound of claim 1, wherein (CR¹R²)_(m)together is selected from the group consisting of methylene, ethylene,propylene and iso-propylene.
 5. A compound of the formula I:

wherein: (CR¹R²)_(m)-Z together is selected from the group consisting of—CH₂CH═CH₂, —CH₂C≡CH, —CH₂C≡CCH₃ or —CH₂CH₂C≡CH; Y is —CR³R⁴R⁵ or NR⁴R⁵;R³ is selected from the group consisting of hydrogen, halo, —OR^(a),SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₃–C₈)cycloalkyl, heterocycle, hetrocycle(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³ can be absent;R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated, mono-, bi- or tricyclic or aromaticring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein thering atoms are optionally interrupted by 1, 2, 3 or 4 heteroatomsselected from the group consisting of —O—, —S—, —SO—, —S(O)₂— or amine(—NR^(a)—) in the ring, wherein any ring comprising R⁴ and R⁵ isoptionally further substituted with from 1 to 14 R⁶ groups; wherein eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene-; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and nis 0, 1, 2 or 3; or a pharmaceutically acceptable salt thereof,optionally in the form of a single stereoisomer or mixture ofstereoisomers thereof.
 6. The compound of claim 1, wherein (CR¹R²)_(m)-Ztogether is —CH₂C≡CH.
 7. The compound of claim 1, wherein R₁ and R₂ arehydrogen or are absent, m is 2 to 8 and the group (CR¹R²)_(m) optionallycomprises 1 to 4 alkenyl or alkynyl conjugated or unconjugated groups.8. The compound of claim 1, wherein m is 1 to 8 and Z is selected fromthe group consisting of —NH₂, —SH, —NR^(a)R^(b), —SR^(a) and cyano. 9.The compound of claim 1, wherein Z is an aryl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, or (C₆–C₂₀)polycyclyl, wherein the ring atoms areoptionally interrupted by 1 to 8 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(a)—).
 10. Acompound of the formula I:

wherein: Z is selected from the group consisting of cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl ringoptionally substituted with 1 to 4 substituents of R^(a); Y is —CR³R⁴R⁵or NR⁴R⁵; R¹ and R² are each independently selected from the groupconsisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R¹ and R²are optionally substituted with 1 to 4 substituents of R^(a), whereinthe alkyl is optionally interrupted by 1–4 heteroatoms selected from—O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R¹ and R² areindependently absent, with the proviso that R^(a) is not SH or halogenwhen the R¹ or R² to which R^(a) is bound is halogen, —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R³ is selected from the groupconsisting of hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl, cyano,nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³ can be absent;R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated, mono-, bi- or tricyclic or aromaticring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein thering atoms are optionally interrupted by 1, 2, 3 or 4 heteroatomsselected from the group consisting of —O—, —S—, —SO—, —S(O)₂— or amine(—NR^(a)—) in the ring, wherein any ring comprising R⁴ and R⁵ isoptionally further substituted with from 1 to 14 R⁶ groups; wherein eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when n is 0, Y is not—NR⁴R⁵; or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof. 11.The compound of claim 10, wherein Z is selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, wherem is 0 or
 1. 12. The compound of claim 10, wherein Z is cyclopentyl andwhere m is
 0. 13. The compound of claim 10, wherein Z is cyclobutyl, mis 1 and R¹ and R² are hydrogen.
 14. A compound of formula I:

wherein Y is selected from the group consisting of

wherein Y optionally comprises 1, 2 or 3 double bonds; each carbon inthe ring is optionally replaced by or interrupted by 1 to 6 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂—, or amino (—NR^(a)—), and isoptionally further substituted with from 1 to 10 R⁶ groups, providedthat the Y or Z ring is not attached at a bridgehead carbon atom or at atrisubstituted carbon atom; Z is selected from the group consisting ofhalogen, vinyl, allyl, 1-propenyl, isopropenyl, ethynyl, 1-propynyl,2-propynyl, 1,3-bytadienyl, penta-1,3-dienyl, penta-1,4-dienyl,hexa-1,3-dienyl, hexa-1,3,5-trienyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, (C₆–C₂₀)polycyclyl, heterocyclyl,cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heterocyclyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —NR^(a)R^(b), —SR^(a), cyano, nitro,trifluoromethyl, trifluoromethoxy, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)NR^(a)—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)NR^(b)—, R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—,R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, —OS(O₂)R^(a),—OS(═O)OR^(a), —OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b); R¹ and R² are eachindependently selected from the group consisting of hydrogen, halogen,—NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl andaryl(C₁–C₈)alkyl, wherein R¹ and R² are optionally substituted with 1 to4 substituents of R^(a), wherein the alkyl is optionally interrupted by1–4 heteroatoms selected from —O—, —S—, —SO—, —S(O)₂— or amino(—NR^(a)—), or where R¹ and R² are independently absent, with theproviso that R^(a) is not SH or halogen when the R¹ or R² to which R^(a)is bound is halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃;R⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene-; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is nothalogen, cyano, or nitro or attached via a heteroatom; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 15. A compoundof formula I:

wherein R¹ and R² are hydrogen, m is 0, 1, 2 or 3 and Z is the moietyderived from the ring selected from the group consisting of furan,dihydro-furan, thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline,pyrrolidine, 1,3-dioxolane, oxazole, thiazole, imidazole,dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline,pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole,2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane,thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane,wherein each Z group is optionally substituted with from 1 to 10 R^(a)groups; Y is —CR³R⁴R⁵ or NR⁴R⁵; R³ is selected from the group consistingof hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³ can be absent;R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated, mono-, bi- or tricyclic or aromaticring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein thering atoms are optionally interrupted by 1, 2, 3 or 4 heteroatomsselected from the group consisting of —O—, —S—, —SO—, —S(O)₂— or amine(—NR^(a)—) in the ring, wherein any ring comprising R⁴ and R⁵ isoptionally further substituted with from 1 to 14 R⁶ groups; wherein eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when n is 0, Z is notattached via a heteroatom, and when n is 0, Y is not —NR⁴R⁵; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 16. Thecompound of claim 15, wherein R¹ and R² are hydrogen, m is 0 or 1, and Zis the moiety derived from the ring selected from the group consistingof furan, thiophene, pyrrole, 2H-pyrrole, oxazole, thiazole, imidazole,pyrazole, isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole and 1H-tetrazole,wherein each Z group is optionally substituted with from 1 to 3 R^(a)groups selected from the group consisting of methyl, ethyl, propyl,iso-propyl, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ and —SCH₃.
 17. Thecompound of claim 1, wherein Z is selected from the group consisting of—CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, R^(a)OC(═S)—,R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(O₂)—, —OS(═O)OR^(a),—OS(O₂)OR^(a) and —OS(O₂)NR^(a)R^(b), wherein m is 1 to
 8. 18. Thecompound of claim 17, wherein Z is selected from the group consisting of—CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, R^(a)OC(═S)—,R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, R^(a)S(═O)₂—, —OS(O₂)R^(a),—OS(═O)OR^(a), —OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b), and wherein(R¹R²)_(m) together is selected from the group consisting of —CH₂—,—CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂CH₂—, —CH═CHCH₂—, —CH₂CH═CH—, —CH═CHCH₂CH₂—,—CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, —C≡CCH₂—, —CH₂C≡C—, —C≡CCH₂CH₂—,—CH₂C≡CCH₂— and —CH₂CH₂C≡C—.
 19. The compound of claim 17, wherein Z is—CO₂R^(a), R^(a)C(═O)—, R^(a)R^(b)N—, R^(a)OC(═S)—, R^(a)C(═S)—,R^(a)S(═O)—, R^(a)S(═O)₂—, —OS(O₂)R^(a), —OS(═O)OR^(a), —OS(O₂)OR^(a),or —OS(O₂)NR^(a)R^(b), and wherein (CR¹R²)_(m) together is selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—,—CH₂CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂CH₂—, —CH═CHCH₂—, —CH₂CH═CH—,—CH═CHCH₂CH₂—, —CH₂CH═CHCH₂—, —CH₂CH₂CH═CH—, —C≡CCH₂—, —CH₂C≡C—,—C≡CCH₂CH₂—, —CH₂C≡CCH₂— and —CH₂CH₂C≡C—.
 20. The compound of claim 1,wherein each R⁹ is independently selected from the group consisting ofhydrogen, halo, —OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocyclyl,hetrocyclyl(C₁–C₈)alkylene-, aryl, aryl(C₁–C₈)alkylene-, heteroaryl,heteroaryl(C₁–C₈)alkylene-, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—.
 21. The compound of claim 1, wherein R³ isselected from the group consisting of hydrogen, halo, —OR^(a), —SR^(a),cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S), SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; or if the ring formed from the groupCR³R⁴R⁵ is aryl or heteroaryl or partially unsaturated then R³ can beabsent.
 22. The compound of claim 1, wherein R³ is selected from thegroup consisting of hydrogen, OH, OCH₃, OAc, NH₂, NHCH₃, N(CH₃)₂ andNHAc.
 23. The compound of claim 22, wherein R³ is hydrogen or OH. 24.The compound of claim 1, wherein R⁴ and R⁵ together with the atom towhich they are attached form a saturated or partially unsaturated,mono-, bi- or tricyclic ring, or aromatic ring having 3, 4, 5, 6, 7, 8,9, 10, 11 or 12 ring atoms, wherein the ring atoms are optionallyinterrupted by 1, 2, 3 or 4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— or amine (—NR^(a)—) in the ring,wherein any ring comprising R⁴ and R⁵ is optionally further substitutedwith from 1 to 14 R⁶ groups; wherein each R⁶ is independently selectedfrom the group consisting of halo, —OR^(a), —SR^(a), (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₁–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring.
 25. The compound of claim 24, wherein the ringcomprising R⁴ and R⁵ and the atom to which they are attached is selectedfrom the group consisting of cyclopentane, cyclohexane, piperidine,dihydro-pyridine, tetrahydro-pyridine, pyridine, piperazine, decaline,tetrahydro-pyrazine, dihydro-pyrazine, pyrazine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, imidazole,dihydro-imidazole, imidazolidine, pyrazole, dihydro-pyrazole,pyrazolidine, norbornane and adamantane, each unsubstituted orsubstituted.
 26. The compound of claim 25, wherein the ring comprisingR⁴ and R⁵ and the atom to which they are attached is selected from thegroup consisting of cyclohexane, piperidine, piperazine, norbornane,adamantane, each unsubstituted or substituted.
 27. The compound of claim1, wherein each R⁶ is independently selected from the group consistingof substituted or unsubstituted (C₁–C₈)alkyl, —OR^(a), —CO₂R^(a),R^(a)C(═O)—, R^(a)C(═O)O—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)— and aryl,provided that when the ring comprising R⁴ and R⁵ contains a ringheteroatom that is O or S, the ring heteroatom that is O or S is notsubstituted with R⁶.
 28. The compound of claim 1, wherein each R⁶ isindependently selected from the group consisting of OH, OCH₃, methyl,ethyl, t-butyl, —CO₂R^(a), —CONR^(a)R^(b), OAc, NH₂, NHCH₃, N(CH₃)₂,NHEt and N(Et)₂, provided that when the ring comprising R⁴ and R⁵contains a ring heteroatom that is O or S, the ring heteroatom that is Oor S is not substituted with R⁶.
 29. The compound of claim 28, whereineach R⁶ is independently selected from the group consisting of methyl,ethyl, —CO₂R^(a), —CONR^(a)R^(b) and OAc, provided that when the ringcomprising R⁴ and R⁵ contains a heteroatom, the heteroatom is notsubstituted with OAc.
 30. The compound of claim 1, wherein number of R⁶groups substituted on the R⁴R⁵ ring is from 1 to
 4. 31. A compound offormula I:

wherein R⁷ and R⁸ are each independently selected from the groupconsisting of hydrogen, (C₁–C₈)alkyl-, aryl(C₁–C₈)alkylene-, mono- orbicyclic-, aromatic or nonaromatic ring having 3, 4, 5, 6, 7, 8, 9 or 10ring atoms, wherein the ring atoms are optionally interrupted by 1, 2, 3or 4 heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, and each is optionallysubstituted with from 1, 2, 3 or 4 R^(a) groups; Y is —CR³R⁴R⁵ or NR⁴R⁵;Z is selected from the group consisting of halogen, vinyl, allyl,1-propenyl, isopropenyl, ethynyl, 1-propynyl, 2-propynyl,1,3-bytadienyl, penta-1,3-dienyl, penta-1,4-dienyl, hexa-1,3-dienyl,hexa-1,3,5-trienyl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,(C₆–C₂₀)polycyclyl, heterocyclyl, cycloalkyl(C₁–C₈)alkyl,bicycloalkyl(C₆–C₁₂)alkyl, heterocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —NR^(a)R^(b),—SR^(a), cyano, nitro, trifluoromethyl, trifluoromethoxy, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)NR^(a)—, R^(a)R^(b)NC(═O)—, R^(a)C(═O)NR^(b)—,R^(a)R^(b)NC(═O)NR^(b)—, R^(a)R^(b)NC(═S)NR^(b)—, R^(a)OC(═S)—,R^(a)C(═S)—, —SSR^(a), R^(a)S(═O)—, —OS(O₂)R^(a), —OS(═O)OR^(a),—OS(O₂)OR^(a) and —O(SO₂)NR^(a)R^(b); R¹ and R² are each independentlyselected from the group consisting of hydrogen, halogen, —NH₂, —OH, —SH,—NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl,wherein R¹ and R² are optionally substituted with 1 to 4 substituents ofR^(a), wherein the alkyl is optionally interrupted by 1–4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R¹and R² are independently absent, with the proviso that R^(a) is not SHor halogen when the R¹ or R² to which R^(a) is bound is halogen, —NH₂,—OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R³ is selected from thegroup consisting of hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; or if the ring formed from the groupCR³R⁴R⁵ is aryl or heteroaryl or partially unsaturated, then R³ can beabsent; R⁴ and R⁵ together with the atoms to which they are attachedform a saturated or partially unsaturated, mono-, bi- or tricyclic oraromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms,wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, wherein any ring comprising R⁴and R⁵ is optionally further substituted with from 1 to 14 R⁶ groups;wherein each R⁶ is independently selected from the group consisting ofhalo, —OR^(a), —SR^(a), substituted or unsubstituted (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when m is 0, Z is nothalogen, cyano, or nitro or is not attached via a heteroatom, and when nis 0, Y is not —NR⁴R⁵; or a pharmaceutically acceptable salt thereof,optionally in the form of a single stereoisomer or mixture ofstereoisomers thereof.
 32. The compound of claim 31, wherein R⁷ isselected from the group consisting of hydrogen, methyl, ethyl, propyl,butyl, 3-pentyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, phenyland benzyl.
 33. The compound of claim 32, wherein R⁷ is hydrogen,methyl, 3-pentyl or sec-butyl.
 34. The compound of claim 1, wherein—NR⁷R⁸ is selected from the group consisting of amino, methylamino,dimethylamino, ethylamino, 3-pentylamino, (diphenylethyl)-amino,(pyridylmethyl)-amino, diethylamino and benzylamino.
 35. The compound ofclaim 34, wherein —NR⁷R⁸ is selected from the group consisting of amino,methylamino, dimethylamino, ethylamino, diethylamino, 3-pentylamino andbenzylamino.
 36. The compound of claim 35, wherein —NR⁷R⁸ is amino. 37.The compound of claim 31, wherein R⁷ is selected from the groupconsisting of benzyl, phenethyl, phenylpropyl and each is optionallysubstituted with from 1, 2 or 3 substituents of R^(a).
 38. The compoundof claim 37, wherein R⁷ is selected from the group consisting of benzyl,phenethyl, phenylpropyl and each is optionally substituted with from 1,2 or 3 substituents of R^(a) selected from the group consisting ofmethyl, ethyl, propyl, and methoxy.
 39. The compound of claim 38,wherein R⁷ is benzyl and R^(a) is methoxy.
 40. The compound of claim 1,wherein R⁹ is independently selected from the group consisting ofhydrogen, fluoro, —OH, —CH₂OH, —OCH₃, —NH₂, —NHCH₃, and —N(CH₃)₂. 41.The compound of claim 40, wherein R⁹ is independently hydrogen or OH.42. The compound of claim 1, wherein each R¹⁰ is independently selectedfrom the group consisting of hydrogen, fluoro, (C₁–C₈)alkyl, aryl, andaryl(C₁–C₈)alkylene-.
 43. The compound of claim 42, wherein R¹⁰ isindependently selected from the group consisting of hydrogen,(C₁–C₈)alkyl, and benzyl.
 44. The compound of claim 43, wherein R¹⁰ ishydrogen.
 45. The compound of claim 1, wherein R^(a) and R^(b) are eachindependently selected from the group consisting of hydrogen,(C₁–C₄)alkyl, aryl and aryl(C₁–C₈)alkylene.
 46. The compound of claim45, wherein R^(a) and R^(b) are each independently selected from thegroup consisting of hydrogen, methyl, ethyl, phenyl and benzyl.
 47. Thecompound of claim 45, wherein R^(a) is (C₁–C₈)alkyl.
 48. The compound ofclaim 47, wherein R^(a) is selected from the group consisting of methyl,ethyl, propyl and butyl.
 49. The compound of claim 1, wherein Y is—CR³R⁴R⁵ or NR⁴R⁵, and is selected from the group consisting of:

wherein q is 0, 1, 2, 3 or 4; R³ is selected from the group consistingof hydrogen, halo, —OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—; and each R⁶ is independently selected fromthe group consisting of halo, —OR^(a), —SR^(a), substituted orunsubstituted (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₁–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl, heterocycle,hetrocyclyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), andR^(a)S(═O)—, provided that R⁶ is not halogen or a heteroatom when R⁶ isattached to a heteroatom.
 50. The compound of claim 1, wherein Y is—CR³R⁴R⁵ or NR⁴R⁵ and is selected from the group consisting of:

wherein R³ is selected from the group consisting of hydrogen, halo,—OR^(a), —SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b)), R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; and each R⁶ is independently selectedfrom the group consisting of halo, —OR^(a), —SR^(a), substituted orunsubstituted (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl,trifluoromethoxy, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl, heterocycle,hetrocyclyl(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), andR^(a)S(═O)—.
 51. The compound of claim 1, wherein the ring formed byR^(a)R^(b) together with the atom to which they are attached is selectedfrom: 2-methylcyclohexan-1-yl, 2,2-dimethylcyclohexan-1-yl,2-ethylcyclohexan-1-yl, 2,2-diethylcyclohexan-1-yl,2-tert-butylcyclohexan-1-yl, 2-phenylcyclohexan-1-yl,3-methylcyclohexan-1-yl, 3-ethylcyclohexan-1-yl,3,3-dimethylcyclohexan-1-yl, 4-methylcyclohexan-1-yl,4-ethylcyclohexan-1-yl, 4,4-dimethylcyclohexan-1-yl,4-tert-butylcyclohexan-1-yl, 4-phenylcyclohexan-1-yl,3,3,5,5-tetramethylcyclohexan-1-yl, 2,4-dimethylcyclopentan-1-yl,4-(carboxyl)cyclohexan-1-yl, 4-(carboxymethyl)cyclohexan-1-yl and4-(carboxyethyl)cyclohexan-1-yl.
 52. The compound of claim 1, whereinthe ring formed by R^(a)R^(b) together with the atom to which they areattached is selected from: piperidin-4-yl, 1-carboxypiperiden-4-yl,1-(methoxycarbonyl)piperidin-4-yl, 1-(ethoxycarbonyl)piperidin-4-yl,1-(n-propoxycarbonyl)piperidin-4-yl,1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,4-carboxypiperiden-1-yl, 4-(methoxycarbonyl)piperidine-1-yl,4-(ethoxycarbonyl)piperidine-1-yl, 4-(n-propoxy)piperidine-1-yl,4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,1-carboxypiperidene-3-yl, 1-(methoxycarbonyl)piperidine-3-yl,1-(ethoxycarbonyl)piperidine-3-yl, 1-(n-propoxycarbonyl)piperidine-3-yl,1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,3-carboxypiperidene-1-yl, 3-(methoxycarbonyl)piperidine-1-yl,3-(ethoxycarbonyl)piperidine-1-yl, 3-(n-propoxycarbonyl)piperidine-1-yl,3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperazin-1-yl,1-caboxypiperazin-4-yl, 1-(methoxycarbonyl)piperazin-4-yl,1-(ethoxycarbonyl)piperazin-4-yl and1-(n-propoxycarbonyl)piperazin-4-yl.
 53. The compound of claim 1,wherein the ring formed by R^(a)R^(b) together with the atom to whichthey are attached is selected from: 2-methylcyclohexan-1-yl,2,2-dimethylcyclohexan-1-yl, 2-ethylcyclohexan-1-yl,2,2-diethylcyclohexan-1-yl, 2-tert-butylcyclohexan-1-yl,2-phenylcyclohexan-1-yl, 3-methylcyclohexan-1-yl,3-ethylcyclohexan-1-yl, 3,3-dimethylcyclohexan-1-yl,4-methylcyclohexan-1-yl, 4-ethylcyclohexan-1-yl,4,4-dimethylcyclohexan-1-yl, 4-tert-butylcyclohexan-1-yl,4-phenylcyclohexan-1-yl, 3,3,5,5-tetramethylcyclohexan-1-yl,2,4-dimethylcyclopentan-1-yl, 4-(carboxyl)cyclohexan-1-yl,4-(carboxymethyl)cyclohexan-1-yl, 4-(carboxyethyl)cyclohexan-1-yl,piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,1-(2,2-dimethylpropoxycarbonyl)piperidin-4-yl, piperidin-1-yl,4-(methoxycarbonyl)piperidine-1-yl,4-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl, piperidin-3-yl,1-(methoxycarbonyl)piperidine-3-yl,1-(2,2-dimethylpropoxycarbonyl)piperidine-3-yl,3-(methoxycarbonyl)piperidine-1-yl and3-(2,2-dimethylpropoxycarbonyl)piperidine-1-yl.
 54. The compound ofclaim 2, wherein Z is an aryl, (C₃–C₈)cycloalkyl, (C₆–C₁₂)bicycloalkyl,or (C₃–C₂₀)polycyclyl, wherein the ring atoms are optionally interruptedby 1–8 heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— and amino (—NR^(a)—).
 55. A compound of formula II:

wherein R¹ and R² are hydrogen, m is 0, 1, 2 or 3 and Z is selected fromthe group consisting of furan, dihydro-furan, thiophene, pyrrole,2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane,oxazole, thiazole, imidazole, dihydro-imidazole, 2-imidazoline,imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine, isoxazole,isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,3-triazole,1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran, 1H-tetrazole, 4H-pyran,pyridine, dihydro-pyridine, tetrahydro-pyridine, piperidine,1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine, pyridazine,pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine,hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine,piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group isoptionally substituted with from 1 to 10 R^(a) groups; L is a linkerselected from the group consisting of —(C₁–C₃)alkyl-C≡C—,—C≡C—(C₁–C₃)alkyl-, —(CH₂)₁₋₃—CH═CH—, —CH═CH—(CH₂)₁₋₃—,—(CH₂)₁₋₂—CH═CH—CH₂— and —CH₂—CH═CH—(CH₂)₁₋₂—; Y is —CR³R⁴R⁵ or NR⁴R⁵;R³ is selected from the group consisting of hydrogen, halo, —OR^(a),SR^(a), (C₁–C₈)alkyl, cyano, nitro, trifluoromethyl, trifluoromethoxy,(C₃–C₈)cycloalkyl, heterocycle, hetrocycle(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; or if the ring formed from the groupCR³R⁴R⁵ is aryl or heteroaryl or partially unsaturated, then R³ can beabsent; R⁴ and R⁵ together with the atoms to which they are attachedform a saturated or partially unsaturated, mono-, bi- or tricyclic oraromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms,wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, wherein any ring comprising R⁴and R⁵ is optionally further substituted with from 1 to 14 R⁶ groups;wherein each R⁶ is independently selected from the group consisting ofhalo, —OR^(a), —SR^(a), substituted or unsubstituted (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a), andR^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when n is 0, Z is notattached via a heteroatom, and when n is 0, Y is not —NR⁴R⁵; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 56. A compoundselected from the group:9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(1);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine(2);9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(3);9-Cyanomethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(4);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-methoxybenzyl)adenine(5);9-(3,4-Dichlorobenzyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(6);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-trifluoromethylbenzyl)adenine(7);9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(8);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-[2-(trifluoromethylphenyl)thiazol-4-ylmethyl]adenine(9);2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-(3-(thiophen-2-yl)prop-2-ynyl)adenine(10);9-Cyclopropylmethyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(14);9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(15);9-Allyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(16);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(propargyl)adenine(17);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pent-4-ynyl)adenine(18);9-(2-Chloroethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(21);9-([1,3]-Dioxolan-2-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(22);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(tetrahydro-pyran-2-ylmethyl)adenine(23);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(isopropylcarboxylate)adenine(24); 9-(Acetic acid ethylester)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(25);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-oxo-oxazolidin-5-ylmethyl)-N6-(3-pentyl)adenine(26);9-Benzyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(27);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)-9-(pyridin-3-ylmethyl)adenine(28);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(4-nitrobenzyl)-N6-(3-pentyl)adenine(29);9-(3,5-Dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-pentyl)adenine(30);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(2-methyl-thiazol-5-ylmethyl)-N6-(3-pentyl)adenine(31);N6-[(S)-(+)-sec-Butyl]-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyl-adenine(32);N6-[(s)-(+)-sec-Butyl]-9-(3,5-dimethyl-isoxazol-4-ylmethyl)-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(33);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(s)-(−)-alpha-napthalen-1-yl-ethyl]-9-(propargyl)adenine(35);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)-9-(propargyl)adenine(36);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N6-(pyridin-2-ylmethyl)adenine(37);2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-[(methyl)(2-phenethyl)]-9-(propargyl)adenine(38);9-Cyclopropylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(45); 9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(46);9-Cyclopentylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(47); 9-Cyclohexylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine(48); 9-Cyclobutyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (49);9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50);2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine (51);2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine;9-(But-3-ynyl)-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (62); and2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine(63); or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 57. Acompound selected from the group in Tables 1 to 7, or a pharmaceuticallyacceptable salt thereof, optionally in the form of a single stereoisomeror mixture of stereoisomers thereof wherein c-Pentyl is cyclopentyl andMe is methyl: TABLE 1

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC100 Propargyl CH₂OH NC101c-Pentyl CH₂OH NC102 Propargyl CO₂H NC103 c-Pentyl CO₂H NC104 PropargylCO₂Me NC105 c-Pentyl CO₂Me NC106 Propargyl CH₂OAc NC107 c-Pentyl CH₂OAcNC108 Propargyl CH₂N(CH₃)₂ NC109 c-Pentyl CH₂N(CH₃)₂ NC110 PropargylCOOCH₂CH₂NHBoc NC111 c-Pentyl COOCH₂CH₂NHBoc NC112 PropargylCOOCH₂CH₂NH₂ NC113 c-Pentyl COOCH₂CH₂NH₂ NC114 Propargyl CONHCH₂CH₃NC115 c-Pentyl CONHCH₂CH₃ NC116 Propargyl CONH₂ NC117 c-Pentyl CONH₂NC118 Propargyl CONHMe NC119 c-Pentyl CONHMe NC120 Propargyl Me, cisCO₂Me NC121 c-Pentyl Me, cis CO₂Me NC122 Propargyl Me, trans CO₂Me NC123c-Pentyl Me, trans CO₂Me NC124 Propargyl CH₂CH₃ NC125 c-Pentyl CH₂CH₃NC128 Propargyl COCH₃ NC129 c-Pentyl COCH₃ NC130 Propargyl CHCH₃(OH)NC131 c-Pentyl CHCH₃(OH)

TABLE 2

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC134 Propargyl CO₂tBu NC135c-Pentyl CO₂tBu NC136 Propargyl CO₂Et NC137 c-Pentyl CO₂Et NC138Propargyl CO₂iBu NC139 c-Pentyl CO₂iBu NC140 Propargyl CO₂iPr NC141c-Pentyl CO₂iPr 63 Propargyl COMe NC142 c-Pentyl COMe NC143 PropargylCOC(CH₃)₃ NC144 c-Pentyl COC(CH₃)₃ NC145 Propargyl COCH₂(CH₃)₃ NC146c-Pentyl COCH₂(CH₃)₃ NC147 Propargyl C(O)N(CH₃)₂ NC148 c-PentylC(O)N(CH₃)₂ NC149 Propargyl C(O)N(CH₃)Et NC150 c-Pentyl C(O)N(CH₃)EtNC142 Propargyl C(O)N(CH₃)iPr NC143 c-Pentyl C(O)N(CH₃)iPr NC144Propargyl C(O)N(CH₃)iBu NC145 c-Pentyl C(O)N(CH₃)iBu NC146 PropargylC(O)NH(CH₃) NC147 c-Pentyl C(O)NH(CH₃) NC148 Propargyl C(O)NH(Et) NC149c-Pentyl C(O)NH(Et) NC150 Propargyl C(O)NH(iPr) NC142 c-PentylC(O)NH(iPr) NC143 Propargyl C(O)NH(iBu) NC144 c-Pentyl C(O)NH(iBu)

TABLE 3

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC153 Propargyl 2-CH₃ NC154c-Pentyl 2-CH₃ NC155 Propargyl 2-C(CH₃)₃ NC156 c-Pentyl 2-C(CH₃)₃ NC157Propargyl 2-C₆H₅ NC158 c-Pentyl 2-C₆H₅ 2 Propargyl 3-CH₃ 3 c-Pentyl3-CH₃ NC159 Propargyl 3-(CH₃)₂ NC160 c-Pentyl 3-(CH₃)₂ NC161 Propargyl3-CH₂CH₃ NC162 c-Pentyl 3-CH₂CH₃ NC163 Propargyl 3-(CH₃)₂, 5-(CH₃)₂NC164 c-Pentyl 3-(CH₃)₂, 5-(CH₃)₂ NC165 Propargyl 4-CH₃ NC166 c-Pentyl4-CH₃ NC167 Propargyl 4-C₂H₅ NC168 c-Pentyl 4-C₂H₅ NC169 Propargyl4-C(CH₃)₃ NC170 c-Pentyl 4-C(CH₃)₃ NC171 Propargyl 4-C₆H₅ NC172 c-Pentyl4-C₆H₅

TABLE 4

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC175 Propargyl cyclohexyl NC176c-Pentyl cyclohexyl NC177 Propargyl CO₂Et NC178 c-Pentyl CO₂Et NC179Propargyl CO₂tBu NC180 c-Pentyl CO₂tBu NC181 Propargyl COMe NC182c-Pentyl COMe NC183 Propargyl CO₂iBu NC184 c-Pentyl CO₂iBu NC185Propargyl 2-Pyrimidinyl NC186 c-Pentyl 2-Pyrimidinyl NC187 PropargylCOC(CH₃)₃ NC188 c-Pentyl COC(CH₃)₃ NC189 Propargyl COMe NC190 c-PentylCOMe NC191 Propargyl COCH₂(CH₃)₃ NC192 c-Pentyl COCH₂(CH₃)₃ NC193Propargyl COCH₃ NC194 c-Pentyl COCH₃ NC195 Propargyl C(O)N(CH₃)₂ NC196c-Pentyl C(O)N(CH₃)₂ NC197 Propargyl C(O)N(CH₃)Et NC198 c-PentylC(O)N(CH₃)Et NC199 Propargyl C(O)N(CH₃)iPr NC200 c-Pentyl C(O)N(CH₃)iPrNC201 Propargyl C(O)N(CH₃)iBu NC202 c-Pentyl C(O)N(CH₃)iBu NC203Propargyl C(O)NH(CH₃) NC204 c-Pentyl C(O)NH(CH₃) NC205 PropargylC(O)NH(Et) NC206 c-Pentyl C(O)NH(Et) NC207 Propargyl C(O)NH(iPr) NC208c-Pentyl C(O)NH(iPr) NC209 Propargyl C(O)NH(iBu) NC210 c-PentylC(O)NH(iBu)

TABLE 5

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC211 Propargyl CH₂OH NC212c-Pentyl CH₂OH NC213 Propargyl CO₂H NC214 c-Pentyl CO₂H NC215 PropargylCO₂Me NC216 c-Pentyl CO₂Me NC217 Propargyl CO₂Et NC218 c-Pentyl CO₂EtNC219 Propargyl CH₂OAc NC220 c-Pentyl CH₂OAc NC221 Propargyl CH₂N(CH₃)₂NC222 c-Pentyl CH₂N(CH₃)₂ NC223 Propargyl COOCH₂CH₂NHBoc NC224 c-PentylCOOCH₂CH₂NHBoc NC225 Propargyl COOCH₂CH₂NH₂ NC226 c-Pentyl COOCH₂CH₂NH₂NC227 Propargyl CONHCH₂CH₃ NC228 c-Pentyl CONHCH₂CH₃ NC229 PropargylCONH₂ NC230 c-Pentyl CONH₂ NC231 Propargyl CONHMe NC232 c-Pentyl CONHMeNC233 Propargyl CH₂CH₃ NC234 c-Pentyl CH₂CH₃ NC235 Propargyl COCH₃ NC236c-Pentyl COCH₃ NC237 Propargyl CHCH₃(OH) NG238 c-Pentyl CHCH₃(OH)

TABLE 6

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z R⁶ NC239 Propargyl CH₂OH NC240c-Pentyl CH₂OH NC241 Propargyl CO₂H NC242 c-Pentyl CO₂H NC243 PropargylCO₂Me NC244 c-Pentyl CO₂Me NC245 Propargyl CH₂OAc NC246 c-Pentyl CH₂OAcNC247 Propargyl CH₂N(CH₃)₂ NC248 c-Pentyl CH₂N(CH₃)₂ NC249 PropargylCOOCH₂CH₂NHBoc NC250 c-Pentyl COOCH₂CH₂NHBoc NC251 PropargylCOOCH₂CH₂NH₂ NC252 c-Pentyl COOCH₂CH₂NH₂ NC253 Propargyl CONHCH₂CH₃NC254 c-Pentyl CONHCH₂CH₃ NC255 Propargyl CONH₂ NC256 c-Pentyl CONH₂NC257 Propargyl CONHMe NC258 c-Pentyl CONHMe NC259 Propargyl CH₂CH₃NC260 c-Pentyl CH₂CH₃ NC261 Propargyl COCH₃ NC262 c-Pentyl COCH₃ NC263Propargyl CHCH₃(OH) NC264 c-Pentyl CHCH₃(OH)

TABLE 7

R⁷, R⁸ = H Compound (CR¹R²)_(m)-Z W W′ R⁶ NC265 Propargyl CH CH CO₂MeNC266 c-Pentyl CH N CO₂Me NC267 Propargyl N CH CO₂Me NC268 c-Pentyl N NCO₂Me NC269 Propargyl CH CH CO₂Me NC270 c-Pentyl CH N CO₂Me NC271Propargyl N CH CO₂Me NC272 c-Pentyl N N CO₂Me NC273 Propargyl CH CHCH₂OH NC274 c-Pentyl CH N CH₂OH NC275 Propargyl N CH CH₂OH NC276c-Pentyl N N CH₂OH NC277 Propargyl CH CH CH₂OH NC278 c-Pentyl CH N CH₂OHNC279 Propargyl N CH CH₂OH NC280 c-Pentyl N N CH₂OH NC281 Propargyl CHCH CO₂H NC282 c-Pentyl CH N CO₂H NC283 Propargyl N CH CO₂H NC284c-Pentyl N N CO₂H NC285 Propargyl CH CH CO₂H NC286 c-Pentyl CH N CO₂HNC287 Propargyl N CH CO₂H NC288 c-Pentyl N N CO₂H NC289 Propargyl CH CHCH₂OAc NC290 c-Pentyl CH N CH₂OAc NC291 Propargyl N CH CH₂OAc NC292c-Pentyl N N CH₂OAc NC293 Propargyl CH CH CH₂OAc NC294 c-Pentyl CH NCH₂OAc NC295 Propargyl N CH CH₂OAc NC296 c-Pentyl N N CH₂OAc NC297Propargyl CH CH CONH₂ NC298 c-Pentyl CH N CONH₂ NC299 Propargyl N CHCONH₂ NC300 c-Pentyl N N CONH₂ NC301 Propargyl CH CH CONH₂ NC302c-Pentyl CH N CONH₂ NC303 Propargyl N CH CONH₂ NC304 c-Pentyl N N CONH₂NC305 Propargyl CH CH CONHMe NC306 c-Pentyl CH N CONHMe NC307 PropargylN CH CONHMe NC308 c-Pentyl N N CONHMe NC309 Propargyl CH CH CONHMe NC310c-Pentyl CH N CONHMe NC311 Propargyl N CH CONHMe NC312 c-Pentyl N NCONHMe NC313 Propargyl CH CH CO₂tBu NC314 c-Pentyl CH N CO₂tBu NC315Propargyl N CH CO₂tBu NC316 c-Pentyl N N CO₂tBu NC317 Propargyl CH CHCO₂tBu NC318 c-Pentyl CH N CO₂tBu NC319 Propargyl N CH CO₂tBu NC320c-Pentyl N N CO₂tBu NC321 Propargyl CH CH CO₂Et NC322 c-Pentyl CH NCO₂Et NC323 Propargyl N CH CO₂Et NC324 c-Pentyl N N CO₂Et NC325Propargyl CH CH CO₂Et NC326 c-Pentyl CH N CO₂Et NC327 Propargyl N CHCO₂Et NC328 c-Pentyl N N CO₂Et NC329 Propargyl CH CH CO₂iBu NC330c-Pentyl CH N CO₂iBu NC331 Propargyl N CH CO₂iBu NC332 c-Pentyl N NCO₂iBu NC333 Propargyl CH CH CO₂iBu NC334 c-Pentyl CH N CO₂iBu NC335Propargyl N CH CO₂iBu NC336 c-Pentyl N N CO₂iBu NC337 Propargyl CH CHCO₂iPr NC338 c-Pentyl CH N CO₂iPr NC339 Propargyl N CH CO₂iPr NC340c-Pentyl N N CO₂iPr NC341 Propargyl CH CH CO₂iPr NC342 c-Pentyl CH NCO₂iPr NC343 Propargyl N CH CO₂iPr NC344 c-Pentyl N N CO₂iPr NC345Propargyl CH CH COMe NC346 c-Pentyl CH N COMe NC347 Propargyl N CH COMeNC348 c-Pentyl N N COMe NC349 Propargyl CH CH COMe NC350 c-Pentyl CH NCOMe NC351 Propargyl N CH COMe NC352 c-Pentyl N N COMe NC353 PropargylCH CH COC(CH₃)₃ NC354 c-Pentyl CH N COC(CH₃)₃ NC355 Propargyl N CHCOC(CH₃)₃ NC356 c-Pentyl N N COC(CH₃)₃ NC357 Propargyl CH CH COC(CH₃)₃NC358 c-Pentyl CH N COC(CH₃)₃ NC359 Propargyl N CH COC(CH₃)₃ NC360c-Pentyl N N COC(CH₃)₃ NC361 Propargyl CH CH COCH₂(CH₃)₃ NC362 c-PentylCH N COCH₂(CH₃)₃ NC363 Propargyl N CH COCH₂(CH₃)₃ NC364 c-Pentyl N NCOCH₂(CH₃)₃ NC365 Propargyl CH CH COCH₂(CH₃)₃ NC366 c-Pentyl CH NCOCH₂(CH₃)₃ NC367 Propargyl N CH COCH₂(CH₃)₃ NC368 c-Pentyl N NCOCH₂(CH₃)₃ NC369 Propargyl CH CH C(O)N(CH₃)₂ NC370 c-Pentyl CH NC(O)N(CH₃)₂ NC371 Propargyl N CH C(O)N(CH₃)₂ NC372 c-Pentyl N NC(O)N(CH₃)₂ NC373 Propargyl CH CH C(O)N(CH₃)₂ NC374 c-Pentyl CH NC(O)N(CH₃)₂ NC375 Propargyl N CH C(O)N(CH₃)₂ NC376 c-Pentyl N NC(O)N(CH₃)₂ NC377 Propargyl CH CH C(O)N(CH₃)Et NC378 c-Pentyl CH NC(O)N(CH₃)Et NC379 Propargyl N CH C(O)N(CH₃)Et NC380 c-Pentyl N NC(O)N(CH₃)Et NC381 Propargyl CH CH C(O)N(CH₃)Et NC382 c-Pentyl CH NC(O)N(CH₃)Et NC383 Propargyl N CH C(O)N(CH₃)Et NC384 c-Pentyl N NC(O)N(CH₃)Et NC385 Propargyl CH CH C(O)N(CH₃)iPr NC386 c-Pentyl CH NC(O)N(CH₃)iPr NC387 Propargyl N CH C(O)N(CH₃)iPr NC388 c-Pentyl N NC(O)N(CH₃)iPr NC389 Propargyl CH CH C(O)N(CH₃)iPr NC390 c-Pentyl CH NC(O)N(CH₃)iPr NC391 Propargyl N CH C(O)N(CH₃)iPr NC392 c-Pentyl N NC(O)N(CH₃)iPr NC393 Propargyl CH CH C(O)N(CH₃)iBu NC394 c-Pentyl CH NC(O)N(CH₃)iBu NC395 Propargyl N CH C(O)N(CH₃)iBu NC396 c-Pentyl N NC(O)N(CH₃)iBu NC397 Propargyl CH CH C(O)N(CH₃)iBu NC398 c-Pentyl CH NC(O)N(CH₃)iBu NC399 Propargyl N CH C(O)N(CH₃)iBu NC400 c-Pentyl N NC(O)N(CH₃)iBu NC401 Propargyl CH CH C(O)NH(Et) NC402 c-Pentyl CH NC(O)NH(Et) NC403 Propargyl N CH C(O)NH(Et) NC404 c-Pentyl N N C(O)NH(Et)NC405 Propargyl CH CH C(O)NH(Et) NC406 c-Pentyl CH N C(O)NH(Et) NC407Propargyl N CH C(O)NH(Et) NC408 c-Pentyl N N C(O)NH(Et) NC409 PropargylCH CH C(O)NH(iPr) NC410 c-Pentyl CH N C(O)NH(iPr) NC411 Propargyl N CHC(O)NH(iPr) NC412 c-Pentyl N N C(O)NH(iPr) NC413 Propargyl CH CHC(O)NH(iPr) NC414 c-Pentyl CH N C(O)NH(iPr) NC415 Propargyl N CHC(O)NH(iPr) NC416 c-Pentyl N N C(O)NH(iPr) NC417 Propargyl CH CHC(O)NH(iBu) NC418 c-Pentyl CH N C(O)NH(iBu) NC419 Propargyl N CHC(O)NH(iBu) NC420 c-Pentyl N N C(O)NH(iBu) NC421 Propargyl CH CHC(O)NH(iBu) NC422 c-Pentyl CH N C(O)NH(iBu) NC423 Propargyl N CHC(O)NH(iBu) NC424 c-Pentyl N N C(O)NH(iBu) NC425 Propargyl CH CHCH₂OCOCH₃ NC426 c-Pentyl CH N CH₂OCOCH₃ NC427 Propargyl N CH CH₂OCOCH₃NC428 c-Pentyl N N CH₂OCOCH₃ NC429 Propargyl CH CH CH₂OCOCH₃ NC430c-Pentyl CH N CH₂OCOCH₃ NC431 Propargyl N CH CH₂OCOCH₃ NC432 c-Pentyl NN CH₂OCOCH₃ NC433 Propargyl CH CH CH₂OCOEt NC434 c-Pentyl CH N CH₂OCOEtNC435 Propargyl N CH CH₂OCOEt NC436 c-Pentyl N N CH₂OCOEt NC437Propargyl CH CH CH₂OCOEt NC438 c-Pentyl CH N CH₂OCOEt NC439 Propargyl NCH CH₂OCOEt NC440 c-Pentyl N N CH₂OCOEt NC441 Propargyl CH CH CH₂OCOiPrNC442 c-Pentyl CH N CH₂OCOiPr NC443 Propargyl N CH CH₂OCOiPr NC444c-Pentyl N N CH₂OCOiPr NC445 Propargyl CH CH CH₂OCOiPr NC446 c-Pentyl CHN CH₂OCOiPr NC447 Propargyl N CH CH₂OCOiPr NC448 c-Pentyl N N CH₂OCOiPrNC449 Propargyl CH CH CH₂OCOiBu NC450 c-Pentyl CH N CH₂OCOiBu NC451Propargyl N CH CH₂OCOiBu NC452 c-Pentyl N N CH₂OCOiBu NC453 Propargyl CHCH CH₂OCOiBu NC454 c-Pentyl CH N CH₂OCOiBu NC455 Propargyl N CHCH₂OCOiBu NC456 c-Pentyl N N CH₂OCOiBu


58. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 1, and a pharmaceutically acceptableexcipient.
 59. The compound of claim 1, or a pharmaceutically acceptablesalt thereof, in the form of a single stereoisomer or mixture ofstereoisomers thereof.
 60. A method for stimulating motor activitywithout dyskinesia in a mammal, comprising administering atherapeutically effective amount of an A_(2A) anatagonist compound ofclaim 1 to the mammal in need of such treatment.
 61. The method of claim60, wherein the mammal suffers from a disorder selected fromHuntington's disease, catalepsy, Parkinson's disease, and narcolepsy.62. The method of claim 60 wherein the mammal suffers from a disorderselected from progressive supernuclear palsy, Huntington's disease,multiple system atrophy, corticobasal degeneration, Wilsons disease,Hallervorden-Spatz disease, progressive pallidal atrophy,Dopa-responsive dystonia-Parkinsonism, spasticity or other disoders ofthe basal ganglia which result in dyskinesias.
 63. A compound of formulaI:

wherein R¹ and R² are hydrogen, m is 0, 1, 2 or 3 and Z is the moietyderived from the ring selected from the group consisting of furan,dihydro-furan, tetrahydrofuran, thiophene, pyrrole, 2H-pyrrole,2-pyrroline, 3-pyrroline, pyrrolidine, 1,3-dioxolane, oxazole, thiazole,imidazole, dihydro-imidazole, 2-imidazoline, imidazolidine, pyrazole,2-pyrazoline, pyrazolidine, isoxazole, isothiazole, 1,2,3-oxadiazole,1,2,4-oxadiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole,2H-pyran, 1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine,tetrahydro-pyridine, piperidine, 1,4-dioxane, morpholine, 1,4-dithiane,thiomorpholine, pyridazine, pyrimidine, dihydro-pyrimidine,tetrahydro-pyrimidine, hexahydro-pyrimidine, pyrazine, dihydro-pyrazine,tetrahydro-pyrazine, piperazine, 1,3,5-triazine and 1,3,5-trithiane,wherein each Z group is optionally substituted with from 1 R^(a) group;Y is —CR³R⁴R⁵ or NR⁴R⁵; R³ is selected from the group consisting ofhydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl, heterocycle,hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, R^(a)S(═O)₂—; or if the ring formed from the group CR³R⁴R⁵is aryl or heteroaryl or partially unsaturated, then R³ can be absent;R⁴ and R⁵ together with the atoms to which they are attached form asaturated or partially unsaturated, mono-, bi- or tricyclic or aromaticring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein thering atoms are optionally interrupted by 1, 2, 3 or 4 heteroatomsselected from the group consisting of —O—, —S—, —SO—, —S(O)₂— or amine(—NR^(a)—) in the ring, wherein any ring comprising R⁴ and R⁵ isoptionally further substituted with from 1 to 14 R⁶ groups; wherein eachR⁶ is independently selected from the group consisting of halo, —OR^(a),—SR^(a), substituted or unsubstituted (C₁–C₈)alkyl, cyano, nitro,trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene-; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and nis 0, 1, 2 or 3, provided that when m is 0, Z is not attached via aheteroatom, and when n is 0, Y is not —NR⁴R⁵; or a pharmaceuticallyacceptable salt thereof, optionally in the form of a single stereoisomeror mixture of stereoisomers thereof.
 64. A compound of formula II:

wherein R¹ and R² are hydrogen, m is 0, 1, 2 or 3 and Z is selected fromthe group consisting of furan, dihydro-furan, tetrahydrofuran,thiophene, pyrrole, 2H-pyrrole, 2-pyrroline, 3-pyrroline, pyrrolidine,1,3-dioxolane, oxazole, thiazole, imidazole, dihydro-imidazole,2-imidazoline, imidazolidine, pyrazole, 2-pyrazoline, pyrazolidine,isoxazole, isothiazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole,1,2,3-triazole, 1,2,4-triazole, 1,3,4-thiadiazole, 2H-pyran,1H-tetrazole, 4H-pyran, pyridine, dihydro-pyridine, tetrahydro-pyridine,piperidine, 1,4-dioxane, morpholine, 1,4-dithiane, thiomorpholine,pyridazine, pyrimidine, dihydro-pyrimidine, tetrahydro-pyrimidine,hexahydro-pyrimidine, pyrazine, dihydro-pyrazine, tetrahydro-pyrazine,piperazine, 1,3,5-triazine and 1,3,5-trithiane, wherein each Z group isoptionally substituted with 1 R^(a) group; L is a linker selected fromthe group consisting of —(C₁–C₃)alkyl-C≡C—, —C≡C—(C₁–C₃)alkyl-,—(CH₂)₁₋₃—CH═CH—, —CH═CH—(CH₂)₁₋₃—, —(CH₂)₁₋₂—CH═CH—CH₂— and—CH₂—CH═CH—(CH₂)₁₋₂—; Y is —CR³R⁴R⁵ or NR⁴R⁵; R³ is selected from thegroup consisting of hydrogen, halo, —OR^(a), SR^(a), (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,heterocycle, hetrocycle(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, heteroaryl,heteroaryl(C₁–C₈)alkyl, —CO₂R^(a), R^(a)C(═O)O—, R^(a)C(═O)—,—OCO₂R^(a), R^(a)R^(b)NC(═O)O—, R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—,R^(a)R^(b)NC(═O)—, R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)—, and R^(a)S(═O)₂—; or if the ring formed from the groupCR³R⁴R⁵ is aryl or heteroaryl or partially unsaturated, then R³ can beabsent; R⁴ and R⁵ together with the atoms to which they are attachedform a saturated or partially unsaturated, mono-, bi- or tricyclic oraromatic ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms,wherein the ring atoms are optionally interrupted by 1, 2, 3 or 4heteroatoms selected from the group consisting of —O—, —S—, —SO—,—S(O)₂— or amine (—NR^(a)—) in the ring, wherein any ring comprising R⁴and R⁵ is optionally further substituted with from 1 to 14 R⁶ groups;wherein each R⁶ is independently selected from the group consisting ofhalo, —OR^(a), —SR^(a), substituted or unsubstituted (C₁–C₈)alkyl,cyano, nitro, trifluoromethyl, trifluoromethoxy, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, heterocycle, hetrocyclyl(C₁–C₈)alkyl, aryl,aryl(C₁–C₈)alkyl, heteroaryl, heteroaryl(C₁–C₈)alkyl, —CO₂R^(a),R^(a)C(═O)O—, R^(a)C(═O)—, —OCO₂R^(a), R^(a)R^(b)NC(═O)O—,R^(b)OC(═O)N(R^(a))—, R^(a)R^(b)N—, R^(a)R^(b)NC(═O)—,R^(a)C(═O)N(R^(b))—, R^(a)R^(b)NC(═O)N(R^(b))—,R^(a)R^(b)NC(═S)N(R^(b))—, R^(a)OC(═S)—, R^(a)C(═S)—, —SSR^(a),R^(a)S(═O)— or two R⁶ groups and the atom to which they are attachedcombined to form C═O or C═S, or wherein two R⁶ groups together with theatom or atoms to which they are attached can form a carbocyclic orheterocyclic ring; R⁷ and R⁸ are each independently hydrogen,(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl, aryl or aryl(C₁–C₈)alkylene,heteroaryl, heteroaryl(C₁–C₈)alkylene; or wherein R⁷ and R⁸ togetherwith the nitrogen atom to which they attach form a heterocycle orheteroaromatic ring; R⁹ and R¹⁰ are each independently selected from thegroup consisting of hydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂,—OCH₃, —SCH₃, (C₁–C₈)alkyl, aryl and aryl(C₁–C₈)alkyl, wherein R⁹ andR¹⁰ are optionally substituted with 1 to 4 substituents of R^(a),wherein the alkyl is optionally interrupted by 1 to 4 heteroatomsselected from —O—, —S—, —SO—, —S(O)₂— or amino (—NR^(a)—), or where R⁹and R¹⁰ are independently absent, with the proviso that R^(a) is not SHor halogen in the case where the R⁹ or R¹⁰ to which R^(a) is bound ishalogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃ or —SCH₃; R^(a) andR^(b) are each independently selected from the group consisting ofhydrogen, halogen, —NH₂, —OH, —SH, —NHCH₃, —N(CH₃)₂, —OCH₃, —SCH₃,propargyl, cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃, —OS(O₂)OCH₃,(C₁–C₈)alkyl, aryl, aryl(C₁–C₈)alkyl, (C₃–C₈)cycloalkyl,(C₆–C₁₂)bicycloalkyl, cycloalkyl(C₁–C₈)alkyl, bicycloalkyl(C₆–C₁₂)alkyl,heteroaryl and heteroaryl(C₁–C₈)alkyl, wherein the alkyl and cycloalkylare optionally interrupted with 1–4 heteroatoms selected from the groupconsisting of —O—, —S—, —SO—, —S(O)₂— and amino (—NR^(c)—); and whereinthe alkyl, cycloalkyl, aryl and heteroaryl are optionally substitutedwith 1, 2, 3 or 4 substituents selected from the group consisting of—OR^(c), —NR^(c)R^(c), SR^(c), cyano, —OS(O₂)H, —OS(O₂)OH, —OS(O₂)CH₃and —OS(O₂)OCH₃, provided that the point of attachment of R^(a) or R^(b)is not a heteroatom when it is attached to another heteroatom; R^(c) isselected from the group consisting of hydrogen and (C₁–C₈)alkyl; and mis 0 to 8; n is 0, 1, 2 or 3, provided that when n is 0, Z is notattached via a heteroatom, and when n is 0, Y is not —NR⁴R⁵; or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 65. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 2, and a pharmaceutically acceptable excipient.66. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 5, and a pharmaceutically acceptableexcipient.
 67. A method for stimulating motor activity withoutdyskinesia in a mammal, comprising administering a therapeuticallyeffective amount of an A_(2A) anatagonist compound of claim 2 to themammal in need of such treatment.
 68. A method for stimulating motoractivity without dyskinesia in a mammal, comprising administering atherapeutically effective amount of an A_(2A) anatagonist compound ofclaim 5 to the mammal in need of such treatment.
 69. A compoundaccording to claim 56, wherein the compound is:2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-propargyladenine(2) or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 70. Acompound according to claim 56, wherein the compound is:9-Cyclopentyl-2-{2-[1(S)-hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}adenine(3) or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 71. Acompound according to claim 56, wherein the compound is:2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-N6-(3-methoxybenzyl)-9-(propargyl)adenine(36) or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 72. Acompound according to claim 56, wherein the compound is:2-{2-[1(S)-Hydroxy-3(R)-methyl-1-cyclohexyl]ethyn-1-yl}-9-(propargyl)-N6-(pyridin-2-ylmethyl)adenine(37) or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 73. Acompound according to claim 56, wherein the compound is:9-Cyclobutylmethyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (46)or a pharmaceutically acceptable salt thereof, optionally in the form ofa single stereoisomer or mixture of stereoisomers thereof.
 74. Acompound according to claim 56, wherein the compound is:9-Cyclopentyl-2-{2-[hydroxy-adamantan-2-yl]ethyn-1-yl}adenine (50) or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 75. A compoundaccording to claim 56, wherein the compound is:2-{2-[Hydroxy-adamantan-2-yl]ethyn-1-yl}-9-propargyl-adenine (51) or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 76. A compoundaccording to claim 56, wherein the compound is:2-{2-[Hydroxy-norbornan-2-yl]ethyn-1-yl}-9-propargyladenine or apharmaceutically acceptable salt thereof, optionally in the form of asingle stereoisomer or mixture of stereoisomers thereof.
 77. A compoundaccording to claim 56, wherein the compound is:2-{3-[1-(Methoxycarbanoyl)piperidin-4-yl]propyn-1-yl}-9-propargyladenine(63) or a pharmaceutically acceptable salt thereof, optionally in theform of a single stereoisomer or mixture of stereoisomers thereof.
 78. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 69, and a pharmaceutically acceptable excipient.79. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 70, and a pharmaceutically acceptableexcipient.
 80. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 71, and a pharmaceuticallyacceptable excipient.
 81. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 72, and apharmaceutically acceptable excipient.
 82. A pharmaceutical compositioncomprising a therapeutically effective amount of a compound of claim 73,and a pharmaceutically acceptable excipient.
 83. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 74, and a pharmaceutically acceptable excipient.
 84. Apharmaceutical composition comprising a therapeutically effective amountof a compound of claim 75, and a pharmaceutically acceptable excipient.85. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of claim 76, and a pharmaceutically acceptableexcipient.
 86. A pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of claim 77, and a pharmaceuticallyacceptable excipient.